Metabolic syndrome is a common condition that can increase complications in breast cancer treatment and increase risk of recurrence. While metformin is a promising therapeutic agent, intensive lifestyle interventions and natural therapies can be safely and effectively implemented in people with metabolic syndrome before they become diabetic. Natural medicine interventions such as exercise, dietary counseling, herbal medicine, and dietary supplementation can help optimize outcomes during and after cancer treatment. Strategies discussed in this article include various diets, management of cortisol levels, sleep, avoidance of obesogenic compounds, and use of the nutrients chromium, zinc, vanadium, magnesium, myo-inositol, alpha lipoic acid, fish oil, vitamin D, CoQ10, L-carnitine, herbal bitters, cinnamon, berberine, and green tea.
Metabolic syndrome affects approximately a third of the general population in the United States.1 Metabolic syndrome and its precursor, insulin resistance, are modifiable risk factors for breast cancer. Metabolic syndrome is associated with a 52% increase in postmenopausal breast cancer risk.2 Breast cancer patients with metabolic syndrome have 3 times the recurrence rate of patients without metabolic syndrome, and metastatic breast cancer patients with metabolic syndrome have poorer outcomes.3 Cancer patients with metabolic syndrome also have more postoperative complications and longer hospital stays. High insulin causes elevations in insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), and aromatase activity, all of which promote breast cancer.5,6 Therefore, when treating the internal terrain to prevent breast cancer occurrence, recurrence, or progression, it is important to effectively screen and treat insulin resistance and metabolic syndrome.
Metformin is currently being investigated as a therapeutic agent in breast cancer. Many observational studies have reported reduced cancer incidence and/or mortality among diabetics receiving metformin (versus other drugs) to treat type 2 diabetes.7 The use of metformin at the time of breast cancer diagnosis has been associated with better clinico-pathological characteristics.8 Additionally, increased pathologic complete response rates to chemotherapy have been observed in diabetic breast cancer patients receiving metformin (24%) compared to diabetics not receiving metformin (8%).9 Despite these encouraging studies, the majority of people cannot receive metformin because it is standard of care only for type II diabetics, not for patients with metabolic syndrome. Natural medicine interventions can play an important role in supporting these patients to optimize their conventional treatments and reduce risk of recurrence.
Breast cancer treatments themselves can exacerbate underlying insulin resistance. Dexamethasone, which is commonly used during breast cancer chemotherapy, causes hyperglycemia. In premenopausal overweight women, use of tamoxifen decreased insulin sensitivity by almost 7 times compared to women not taking tamoxifen.10 In older breast cancer survivors, tamoxifen is associated with an increased incidence of diabetes.11 Furthermore, mood stabilizers such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and atypical antipsychotics can affect food intake and lipid accumulation, leading to obesity.12 On the other hand, many of the natural interventions used routinely as breast cancer adjuncts target metabolic syndrome and address some of the untoward effects of medications. For this reason, it is useful for clinicians to address insulin resistance and metabolic syndrome before, during, and after a breast cancer diagnosis. An interactions chart is provided at the end of this article to address combining interventions with surgery, radiation, chemotherapy, and hormone-blocking medications.
It is important to differentiate between type II diabetes, metabolic syndrome, and insulin resistance. Practitioners occasionally will encounter breast cancer patients who have undiagnosed type 2 diabetics and can encourage or prescribe metformin in this population. More frequently, practitioners encounter undiagnosed metabolic syndrome or insulin resistance that can be reversed through lifestyle interventions and natural therapies.
According to the US Preventive Services Task Force and the American Diabetes Association, diabetes mellitus is diagnosed with:
• A fasting plasma glucose level ≥126 mg/d (7.0 mmol/L)
A diagnosis of metabolic syndrome, according to the US National Cholesterol Education Program Adult Treatment Panel III (2001), requires at least 3 of the following:
• Central obesity: waist circumference ≥88 cm or 35 inches (women), ≥102 cm or 40 inches (men)
• Dyslipidemia: triglycerides (TG) ≥ 150 mg/dL (1.7 mmol/L)
• Dyslipidemia: high-density lipoprotein cholesterol (HDL-C) < 50 mg/dL (women) < 40 mg/dL (men)
• Blood pressure ≥ 130/85 mmHg (or treated for hypertension)
• Fasting plasma glucose ≥ 110 mg/dL (6.1 mmol/L)
Risk factors for metabolic syndrome include age above 40 to 45 years, obesity, abdominal fat, sedentary lifestyle, history of gestational diabetes, and elevated cortisol levels.13
Insulin resistance (IR) is a physiological condition rather than a diagnosis per se. It occurs when the body’s cells have a decreased ability to respond to the action of the insulin, so to compensate, the pancreas secretes more insulin. High insulin levels are associated with higher glucose levels, increased blood pressure, elevated triglycerides and low-density lipoprotein (LDL), and decreased concentrations of HDL.14 The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) is a score that is often used to define IR in research.
There is conflicting research regarding which tests are best used to screen for metabolic syndrome in breast cancer patients and which tests are most predictive of breast cancer occurrence and recurrence risk in this population. In addition, women can sometimes be thin in appearance but still metabolically obese, and this subtype with insulin resistance can be easily missed. Below are the main tests to consider ordering in high-risk breast cancer patients and breast cancer survivors:
• Body mass index (BMI) in kg/m2 = [mass (lb) / (height (in))2] x 703. BMI <25 kg/m2 = normal, ≥25 kg/m2 = overweight/obese. Some research concluded that BMI < 25 kg/m2 reduces risk of recurrence. Other research showed that women who are underweight (BMI <18.5 kg/m2) or morbidly obese (BMI >30 kg/m2) had increased risk of recurrence, whereas normal or overweight women with BMI 18.5–30 kg/m2 have the least risk of recurrence.15
• Fasting insulin: Women are at highest risk for breast cancer in the years leading up to a diabetes diagnosis when insulin levels are high.16 Normal fasting insulin is < 25 μIU/mL. In the Women’s Health Initiative, fasting insulin >8.8 μIU/mL increased risk.17 However, in a 2013 meta-analysis, serum insulin was not associated with breast cancer risk when BMI was controlled for.18
• Lipid profile: Patients with metabolic syndrome and elevated triglycerides have increased risk of breast cancer recurrence.19 Ideal ranges may be TG < 100 mg/dL and HDL > 50 mg/dL.
• Hemoglobin A1C (HgA1C): Normal is <6.0%. In theory, ideal range may be <5.5%
• High-sensitivity C-reactive protein (hsCRP): Insulin resistance increases inflammation and CRP.20 Normal is <3.0 mg/L. The ideal range is <1.0 mg/L for cardiovascular risk.
• Vitamin D: Vitamin D deficiency is associated with insulin resistance21 and increased risk of recurrence and death in early-stage breast cancer patients.22 The goal is 40–60 ng/mL (see below).
• Fasting glucose: <100 mg/dL (5.56 mmol/L) is ideal.
Other Related Laboratory Values
C-peptide: The C-peptide test reflects insulin produced by the pancreas only. It is a useful alternative or adjunct to testing for fasting insulin because it is less affected by fasting and can evaluate insulin production in patients on insulin therapy.23 According to one study, in older women, C-peptide >3.09 ng/mL increased breast cancer risk.24 In a 2013 meta-analysis, however, when BMI was controlled for, C-peptide was not associated with breast cancer risk.25 Note that this only applies to primary prevention. Women with an existing breast cancer diagnosis interested in secondary prevention or reducing disease progression may wish to aspire to ideal levels such as <2 ng/mL26 or in women over 55 years of age, <3.09 ng/mL.27
Homeostasis model assessment-estimated insulin resistance (HOMA-IR): This score is used to define insulin resistance in research. HOMA-IR = (fasting glucose in mmol/L x fasting insulin)/22.5 OR (fasting glucose in mg/dL x fasting insulin)/405. HOMA-IR ≥ 2.50 indicates insulin resistance. HOMA-IR showed a positive trend for recurrence in estrogen receptor/progesterone receptor (ER/PR)-negative breast cancer survivors but not ER/PR-positive ones.28 A HOMA-IR calculator is available at www.hcvsociety.org/files/HOMACalc.htm.
Uric acid: Several studies have concluded that high uric acid levels may independently contribute to insulin resistance.29 In theory, the ideal range is <5.5 mg/dL.
Insulin-like growth factor 1 (IGF-1): A meta-analysis with studies published up to 2006 concluded that the association of IGF-1 with breast cancer risk is limited to premenopausal women.30 However, a pooled analysis of 17 prospective studies up to 2010 showed that circulating IGF-1 is positively associated with breast-cancer risk in both pre- and postmenopausal women with ER-positive tumors.31
Homocysteine: Homocysteine levels can increase with age, when a patient smokes, and with some medications. Homocysteine can be elevated in women with DNA sequence variations in folic acid metabolism. This methylenetetrahydrofolate reductase single nucleotide polymorphism (MTHFR SNP) may also impact estrogen metabolism. If breast cancer patients have a history of mood disorders and elevated homocysteine, MTHFR testing is advised.
Adiponectin: The more obese the patient, the lower the adiponectin levels in the blood. Low levels of adiponectin have been associated with an increased incidence of obesity-linked cardiovascular disease, insulin resistance, and type II diabetes. In postmenopausal women, high serum adiponectin was associated with a decreased risk for breast cancer.32 In breast cancer survivors, low adiponectin was associated with an increased risk of recurrence in ER/PR-negative patients but not ER/PR-positive ones.33
Cancer can behave like an annual plant or a perennial plant. Surgery, radiation, and chemotherapy are necessary treatments to remove this plant. However, we must also treat the oncology terrain so that the internal environment is unfavorable to cancer’s return. When metabolic syndrome is part of the oncology terrain, a multifaceted approach that includes exercise, nutrient repletion, diet, and stress management is required.
Exercise decreases insulin resistance, improves mood, lessens fatigue, improves sleep, manages weight, reduces hot flashes, improves immunity, and prevents osteoporosis. Exercise has been shown to improve survivorship in patients with breast, prostate, and colorectal cancer.34 In one study of 3,000 breast cancer survivors, women who exercised 3 to 5 hours per week had almost a 50% reduction in recurrence.35 Ten percent of incident breast cancers are attributed to inactivity. Exercise should be used for primary prevention of breast cancer.36
Exercise decreases insulin resistance, improves mood, lessens fatigue, improves sleep, manages weight, reduces hot flashes, improves immunity, and prevents osteoporosis.
Diet and exercise may be even more powerful than metformin in preventing diabetes. In a large study titled "The Diabetes Prevention Program," high-risk participants were given placebo, metformin, or intensive lifestyle intervention and followed for an average of 3 years. Diabetes incidence was reduced by 58% with intensive lifestyle intervention and by 31% with metformin compared to placebo.37 All 3 groups were then offered group-implemented lifestyle intervention and monitored until 10-year follow-up. Diabetes incidence at 10 years was reduced by 34% in the lifestyle group and 18% in the metformin group, demonstrating that intensive lifestyle intervention is still the most effective treatment for diabetes prevention and that improvements can persist for 10 years.38
A number of different diets may be useful in treating metabolic syndrome, including the Mediterranean diet, the DASH diet, a vegetarian diet, caloric restriction, and a ketogenic diet. Common elements in all of these diets are low sugar and high vegetable intake. Below is a summary of the research on various dietary interventions.
• Removal of simple sugars: soda, high fructose corn syrup, white sugar, and white flour. A low-calorie, low-glycemic diet has been shown to benefit patients with insulin resistance and type 2 diabetes.39,40 Low–glycemic index (GI) foods, by virtue of their slow digestion and absorption, produce gradual rises in blood sugar and insulin levels and reduce insulin levels and insulin resistance. Low-GI diets have been shown to improve both glucose and lipid levels in people with diabetes (type 1 and type 2). A good online resource is www.glycemicindex.com. Foods with a GI >40 are low, with moderate GI being 40 to 60 and high GI being >61 (refined and simple carbohydrates).
• High-fiber diet: Water-soluble fiber lowers the glycemic index of carbohydrates, increases tissue sensitivity to insulin, lowers fasting blood sugar, increases satiety, and improves lipid profiles. Options include psyllium husk powder, flax, oat bran, apple pectin, guar gum, and chia.41–43
• Include stevia: Stevioside, a component in the plant Stevia rebaudiana bertoni, is 25 to 300 times sweeter than sucrose. It has antihyperglycemic, antihypertensive, antiinflammatory, antitumor, antidiarrheal, diuretic, and immune-modulating actions.44,45
• Mediterranean diet: In the DIRECT Study, a 2-year dietary intervention randomized controlled trial (RCT), 322 participants were randomized into groups of Mediterranean, low-fat, or low-carbohydrate diet. Low-carbohydrate and Mediterranean diets had the best outcomes for weight loss, glycemic control, and lipid profiles.46 In another RCT of 90 subjects with abdominal obesity without diabetes, after 2 months on the Mediterranean diet, measurements of HOMA-IR, flow-mediated dilatation, and diastolic blood pressure all decreased in the intervention group while the control group remained unchanged.47
• DASH diet: The DASH diet plan was developed by the US National Institutes of Health to lower blood pressure without medication. The DASH diet is rich in fruits, vegetables, and low-fat or non-fat dairy. It includes grains (especially whole grains), lean meats, fish, poultry, nuts, and beans. It is high in fiber and low to moderate in fat and follows US guidelines for sodium content. In the Insulin Resistance Atherosclerosis Study, 862 participants followed the DASH diet for a year. There were beneficial effects on insulin sensitivity, LDL, and weight.48 The DASH diet also may reduce the risk of colon cancer.49
• Vegetarian diet: In an RCT of 176 overweight adults, participants completed an 18-month trial of vegetarianism that resulted in weight loss, decreased triglycerides, and decreased LDL:HDL ratio.50 High levels of animal protein have been associated with increased levels of cortisol and increased insulin resistance.51
• Caloric restriction: In an RCT of 107 overweight or obese premenopausal women, participants underwent a diet with 25% energy restriction for 6 months, either as intermittent restriction (647 calories/day for 2 days/week) or continuous restriction (1,499 calories/day for 7 days/week). Both groups reduced weight, leptin, hsCRP, total and LDL cholesterol, triglycerides, and blood pressure. Both groups also increased sex hormone binding globulin and IGF binding proteins 1 and 2. Fasting insulin and insulin resistance were reduced in both groups, but the effect was greater with intermittent restriction (P=0.04).52
• Ketogenic diet: In an RCT of 58 obese children and adolescents, participants underwent a ketogenic vs hypocaloric diet for 6 months. Both groups significantly reduced their weight, fat mass, waist circumference, fasting insulin, and HOMA-IR (P=0.009 for ketogenic and P=0.014 for hypocaloric), but the differences were greater in the ketogenic group. Both groups increased whole-body insulin sensitivity index significantly, but only the ketogenic group increased adiponectin significantly.53
Several nutrients have been researched in the treatment and prevention of metabolic syndrome.
• Chromium: Studies were mixed with regard to chromium’s impact on metabolic syndrome. Chromium may increase insulin sensitivity54 and may decrease fasting glucose and HgA1C.55
• Zinc: Zinc is involved in the synthesis, storage, and release of insulin. Studies have shown that zinc deficiency may predispose to glucose intolerance, insulin resistance, and diabetes. Several studies demonstrated the benefit of supplemental zinc for adult and pediatric populations to increase insulin sensitivity. Fifty-six obese women given 30 mg/day zinc daily for 4 weeks had decreased insulin, HOMA-IR, and leptin levels.56
• Vanadium: Several small, non-randomized trials exist on vanadium. Vanadyl sulfate 100 mg daily for 3 weeks improved insulin sensitivity, lowered fasting glucose, and HgA1C in type 2 diabetics.57–59
• Magnesium: High dietary magnesium prevents progression of insulin resistance to diabetes.60,61 In an RCT of overweight, insulin-resistant patients with normal serum magnesium, 52 patients received placebo or 365 mg/day of Mg-aspartate-hydrochloride for 6 months. Magnesium supplementation resulted in a significant improvement of fasting plasma glucose and some insulin sensitivity indices compared to placebo.62
• Inositol: In an RCT of 80 postmenopausal women affected by metabolic syndrome, participants were given placebo or 2 g myo-inositol twice daily for 12 months. With the exception of BMI and waist circumference, all the parameters studied (serum glucose, insulin, HOMA-IR, triglycerides, and total and HDL-C) improved significantly.63 In a recent trial of 155 postmenopausal women affected by metabolic syndrome at risk of breast cancer, the use of 2 g inositol with 100 mg alpha lipoic acid for 6 months reduced HOMA-IR score and improved lipid profiles.64
• Alpha lipoic acid (ALA): Preliminary and double-blind trials have found that supplementing 600 to 1,800 mg of ALA per day improves insulin sensitivity.65
• Vitamin D: A systematic review and meta-analysis of prospective studies on vitamin D and type 2 diabetes and other metabolic outcomes in more than 210,000 participants concluded that relative risk for individuals in top versus bottom thirds of baseline vitamin D were 0.81 (95% CI: 0.71–0.92) for diabetes; 0.86 (95% CI: 0.80–0.92) for metabolic syndrome; and 0.84 (95% CI 0.64–1.12) for insulin resistance.66 In a review of 11 case-controlled studies, a serum vitamin D level of 47 ng/mL was associated with a 50% lower risk of breast cancer.67
• CoQ10: In a double-blind RCT of 74 type 2 diabetics, supplementation with 100 mg CoQ10 twice daily reduced HgA1C and blood pressure.68
• Fish oil: A meta-analysis of 65 published reports showed triglyceride reduction averaging 25% with fish oil consumption of 4 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).69 In addition, treatment of obese patients with 5 g daily fish oil for 3 months increased adinopectin.70
• Carnitine: In an RCT of 258 uncontrolled type 2 diabetics, participants took orlistat plus 2 g L-carnitine daily or orlistat alone. After 12 months, there was improved body weight, glycemic profile, HOMA-IR, LDL, and adiponectin and a faster improvement in fasting plasma insulin, total cholesterol, TG, leptin, tumor necrosis factor alpha (TNF-α), and Hs-CRP in the carnitine group.71
• Contraindication/caution: Glucosamine can aggravate insulin resistance.72
With the exception of cinnamon, almost all herbs traditionally used for blood sugar management are bitters. Bitter herbs can be used to improve mineral absorption while simultaneously improving insulin sensitivity and restoring digestive function. Bitters increase peristalsis everywhere in the digestive tract except the duodenum, where bitters slow peristalsis to allow for better absorption. Bitters stimulate the appetite, while at the same time increasing satiety.73 Common examples of bitters include bitter melon, fenugreek, berberine, green tea, gentian, orange peel, and wormwood.
• Berberine: An RCT of 89 women with insulin resistance and polycystic ovarian syndrome compared 500 mg berberine 3 times daily to metformin or placebo over 3 months. Berberine compared to metformin significantly decreased waist circumference, waist-to-hip ratio, total cholesterol, triglycerides, and LDL and increased HDL and sex hormone–binding globulin. Berberine compared to placebo decreased fasting plasma glucose, fasting insulin, HOMA-IR, and other parameters.74
• Green tea: Green tea improves insulin sensitivity, increases insulin protection, and improves glucose metabolism.75 Green tea also increases glutathione and antioxidant capacity in people with metabolic syndrome.76 In a controlled trial, elderly patients with metabolic syndrome in the intervention group were given 3 of cups green tea daily for 2 months. Green tea was effective in inducing weight loss and reducing BMI and waist circumference.77
• Maitake mushroom: Maitake mushroom, a common cancer adjunct, has demonstrated in animal studies its ability to improve insulin resistance and decrease severity of diabetes.78
• Cinnamon: Cinnamon increases insulin sensitivity by activating insulin receptors. Multiple RCTs suggest that at doses of 360 mg to 6,000 mg daily, cinnamon lowers fasting glucose.79–81
• Holy basil/Tulsi,82 fenugreek/Trigonella foenum-graecum,83,84 and bitter melon/Gymnema85 are other effective insulin-sensitizing herbs.
Sleep deprivation is a common obstacle to cure in insulin resistance. Glucose tolerance is decreased from sleep debt.86 Sleep hygiene strategies include a bedtime routine, sleeping in a completely dark room, avoiding working in the bedroom, sleeping 3 to 5 feet away from outlets and electronic devices, and avoiding caffeine and alcohol before bed.
Cancer diagnosis and treatment, as significant chronic stressors, will commonly cause elevated cortisol and flat diurnal rhythm. High cortisol levels trigger hyperinsulinemia in a negative cycle in which hyperinsulinemia then triggers high cortisol. In oncology, there is growing evidence that flattened diurnal cortisol rhythm accelerates tumor progression. Flattened cortisol curve is associated with significantly earlier death in metastatic breast cancer, predicting survival up to 7 years later.87 Flat cortisol curves are associated with fatigue in long-term breast cancer survivors,88 low white blood cell counts and suppressed activity of natural killer (NK) cells,89 and depression,90 and it suppresses bone growth in survivors taking hormone-blocking medications who are at higher risk for osteoporosis. For all of these reasons, naturopathic medicine has an important role to play in addressing high nighttime cortisol. Strategies include participating in a body-mind-spirit group91 or a cognitive-behavioral stress management class92 and using cortisol-lowering agents such as ashwaghanda, theanine, phosphatidyl serine, magnolia, Eleuthrococcus, Rhodiola, and/or holy basil.
Avoidance of Obesogenic Compounds
Obesogenic compounds are exogenous chemicals that affect the number of fat cells, the size of fat cells, appetite, satiety, food preferences, and energy metabolism.93 Most known or suspected obesogens are also hormone-disrupting chemicals that have been linked to breast cancer. Many obesogens are widespread.94–96 As clinicians, our emphasis is on toxin avoidance and detoxification to help the individual patient. However, when we consider the effect of obesogens and hormone-disrupting chemicals on future generations, it becomes apparent that we have an important role to play in preventive medicine.
Bisphenol-A (BPA) is in polycarbonate plastics found in the lining of canned goods, toys, medical devices, food and beverage containers, dental sealants, and cash register receipts. BPA can seep into food from storage containers at room temperature97 or into the body by handling products made from it. BPA makes fat cells larger, can limit adiponectin, and appears to be an independent risk factor for obesity. In a cross-sectional study of children and adolescents reported in JAMA, urinary BPA concentration was significantly associated with obesity after controlling for race/ethnicity, age, caregiver education, poverty:income ratio, sex, caloric intake, television watching, and urinary creatinine level.98 Another study involving the National Health and Nutrition Examination also showed that children had a positive association between increasing levels of urinary BPA and obesity, independent of other risk factors.99
BPA has also been implicated in the development of breast cancer. Postmenopausal women with high serum levels of BPA and monoethyl phthalate had elevated breast density.100 Exposing prepubertal rats to the xenoestrogen BPA increased breast cancer susceptibility in adulthood.101 Animal studies show that BPA decreases methylation upstream of the Agouti gene, causing epigenetic changes that persist in future generations.102 BPA activates the mammalian target of rapamycin (mTOR) pathway and reduces important cancer checkpoints such as p53, p21, and BAX.103 BPA at environmentally relevant doses may even reduce the efficacy of chemotherapeutic agents. Low nanomolar doses of BPA antagonized the cytotoxicity of doxorubicin, cisplatin, and vinblastine in breast cancer cells.104,105
Personal action steps include avoiding polycarbonate plastics (recycling code #7), canned goods, and dental sealants.106,107
Nicotine in tobacco products and certain insecticides is a developmental obesogen. Epidemiological studies show that children of mothers who smoked during pregnancy are at higher risk of obesity. This has been confirmed by animal studies showing that nicotine during prenatal development is linked with obesity in offspring.108 Similarly, nicotine exposure is implicated in death from breast cancer. In a systematic review of the LACE study plus 7 additional studies, women who smoked following breast cancer diagnosis and treatment were at higher risk of death both from breast cancer (two-fold) and other causes (four-fold).109
Organochlorines: Pesticides, Polyvinylchloride, and Dioxin
Examples of organochlorines include pesticides (eg, DDT [dichlorodiphenyltrichloroethane], Aldrin, Dieldrin, Chlordane), PCB [polychlorinated biphenyls], TCDD (tetrachlorodibenzo-p-dioxin), and the plastic polyvinylchloride (PVC), and dioxin (which is produced in the manufacturing and combustion of chlorine compounds). Organochlorines can be found in nonorganic food, clingwrap, blinds, windows, floorings, wallpaper, weather stripping, electrical cables, artificial leather goods, medical products, and toys. There is evidence for a positive association between diabetes and certain organochlorines such as DDT, DDE, dioxins, and PCBs.110
Organochlorines have also been linked to the development of breast cancer. Multiple studies have shown higher levels of organochlorines in the breast biopsies of women with breast cancer than in women without.111 Population studies investigating the effects of high TCDD dioxin exposure in Seveso, Italy, found that women in the area had an increased risk for breast cancer.112 Occupational exposure to dioxins at a pesticide plant in Germany resulted in significantly increased breast cancer mortality among women workers. At least 16 organochlorines have been found to cause breast cancer in lab animals. Action steps include eating organic when possible, eating lower on the food chain, using a water filter, and avoiding PVC plastic (recycling code #3) in household goods, toys, shower curtains, and raingear.
Phthalates are not organochlorines but are used to soften plastic, especially PVC. They can be found in hydraulic fracking fluids, cosmetics, fragrances, medications, baby care products, building materials, modeling clay, automobiles, cleaning materials, and insecticides. Phthalates are peroxisome proliferator–activated receptor (PPAR) activators, which means they affect adipocyte differentiation, production of adipokines, insulin responsiveness, and other biological processes related to glucose and lipid regulation. Three cross-sectional human studies on phthalates show positive associations with diabetes or obesity.115
Phthalates are also linked to breast cancer. Children of New Zealand soldiers who served in Malaya and had phthalates applied daily to their clothing to prevent tick-transmitted bush typhus had increases in the incidences of hypospadias, cryptorchidism, and breast cancer (P<0.05).116 In an age-matched study in Mexico of 233 women with breast cancer and 221 controls, exposure to diethyl phthalate as measured by urine metabolite levels was associated with increased risk of breast cancer.117
Phthalates in hydraulic fracking fluids may contaminate or may have already contaminated groundwater. As a 2012 JAMA article emphasized, there is a paucity of data evaluating the health impacts of fracking.118 Between 2005 and 2009, companies in the United States used more than 2,500 hydraulic fracturing products containing 750 compounds. More than 650 of these products contained chemicals that are known or possible human carcinogens, regulated under the Safe Drinking Water Act, or listed as hazardous air pollutants. At least 13 were known carcinogens.119 Exposure can be reduced by choosing toxin-free cosmetics and avoiding PVC plastic.
Insulin resistance and metabolic syndrome are major aspects of the oncology terrain that can and should be modified. Common sense strategies like exercise, sleep hygiene, and stress management have proven to be effective in normalizing insulin, blood sugar, and lipids. Additional strategies such as nutrient repletion and herbal medicine can also be incorporated for better clinical outcomes. An overlooked area in breast cancer and obesity prevention is the avoidance of obesogenic compounds. Natural medicine, with its holistic model of care, can play a vital role in identifying and managing insulin resistance to help reduce breast cancer occurrence, recurrence, or progression.
|Intervention for Insulin Resistance||Breast Cancer Primary Prevention||Right Before Breast Surgery||During Radiation||During AC Taxol Chemotherapy||With Tamoxifen or Aromatase Inhibitor|
|Exercise, sleep, stress management, toxin avoidance||Beneficial||Beneficial||Beneficial||Beneficial||Beneficial|
|Low glycemic diet||Beneficial||Beneficial||Beneficial||Beneficial||Beneficial|
|Chromium, zinc, vanadium, inositol, magnesium||Safe||Safe||Safe||Safe||Safe|
|Fish oil||Beneficial122||Caution before surgery,123 Use immediately afterwards124||Beneficial125||Beneficial126-128||Beneficial129,130|
|Alpha lipoic acid||Safe||Safe||Theoretical Caution or Avoid||Theoretical Caution or Avoid||Safe|
|CoQ10||Safe||Safe||Theoretical Caution or Avoid||May be beneficial with adriamycin131||Beneficial132|
|Carnitine||Safe||Safe||Safe||Avoid acetyl L carnitine with docetaxol133||Safe|
|Cinnamon||Safe||Safe||Safe||Theoretical Caution with high dose134||Theoretical Caution with high dose135|
|Berberine||Safe||Safe||May be Beneficial136,137||Theoretical caution138||Caution mixed data139-140|
|Green tea||Beneficial141||Avoid142||May be Beneficial143||Caution mixed data144-149||May be Beneficial150,151|
|Bitters||Safe||Safe||Safe||Avoid if heartburn||Safe|
1. Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003–2006. National Health Statistics Report. 2009;13.
2. Esposito K, Chiodini P, Capuano A, et al. Metabolic syndrome and postmenopausal breast cancer: systematic review and meta-analysis. Menopause. 2013;20(12):1301-1309.
3. Stebbing J, Sharma A, North B, et al. A metabolic phenotyping approach to understanding relationships between metabolic syndrome and breast tumour responses to chemotherapy. Ann Oncol. 2012;23(4):860-866.
4. Lohsiriwat V, Pongsanguansuk W, Lertakyamanee N, Lohsiriwat D. Impact of metabolic syndrome on the short-term outcomes of colorectal cancer surgery. Dis Colon Rectum. 2010;53(2):186-191.
5. Goodwin PJ, Stambolic V. Obesity and insulin resistance in breast cancer--chemoprevention strategies with a focus on metformin. Breast. 2011;20 Suppl 3:S31-S35.
6. Wallace JM. Individualizing nutrition protocols to complement cancer care. 17th International Symposium on Functional Medicine; Carlsbad, CA; May 20-23, 2010.
7. Goodwin PJ, Stambolic V, Lemieux J, et al. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat. 2011;126(1):215-220.
8. Aksoy S, Sendur MA, Altundag K. Demographic and clinico-pathological characteristics in patients with invasive breast cancer receiving metformin. Med Oncol. 2013;30(2):590.
9. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297-3302.
10. Johansson H, Gandini S, Guerrieri-gonzaga A, et al. Effect of fenretinide and low-dose tamoxifen on insulin sensitivity in premenopausal women at high risk for breast cancer. Cancer Res. 2008;68(22):9512-9518.
11. Lipscombe LL, Fischer HD, Yun L, et al. Association between tamoxifen treatment and diabetes: a population-based study. Cancer. 2012;118(10):2615-2622.
12. Chen X, Margolis KJ, Gershon MD, Schwartz GJ, Sze JY. Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake. PLoS ONE. 2012;7(3):e32511.
13. Type 2 diabetes and risk factors. Mayo Clinic website. http://www.mayoclinic.org/diseases-conditions/type-2-diabetes/basics/risk-factors/CON-20031902. Accessed January 12, 2014.
14. Insulin Resistance. Lab Tests Online website. http://labtestsonline.org/understanding/ conditions/insulin-resistance. Accessed January 3, 2014. and Insulin resistance syndrome. WebMD website. http://diabetes.webmd.com/guide/insulin-resistance-syndrome. Accessed January 3, 2014.
15. Poole EM, Shu X, Caan BJ, et al. Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project. Breast Cancer Res Treat. 2013;139(2):529-537.
16. Gaudet MM, Patel AV, Teras LR, et al. Obesity-related markers and breast cancer in CPS-II Nutrition Cohort. Int J Mol Epidemiol Genet. 2013;4(3):156-166.
17. Gunter MJ, Hoover DR, Yu H, et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2009;101(1):48-60.
18. Autier P, Koechlin A, Boniol M, et al. Serum insulin and C-peptide concentration and breast cancer: a meta-analysis. Cancer Causes Control. 2013;24(5):873-883.
19. Alschuler L. Reducing risk of breast cancer by focusing on metabolic parameters. Nat Med J. 2013;5(10). http://www.naturalmedicinejournal.com/article_content.asp?edition=1§ion=3&article=465. Accessed December 20, 2013.
20. Haffner SM. Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol. 2003;92(4A):18J-26J.
21. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79(5):820-825.
22. Rose AA, Elser C, Ennis M, Goodwin PJ. Blood levels of vitamin D and early stage breast cancer prognosis: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013;141(3):331-339.
23. Lab Tests Online. http://www.labtestsonline.org. Accessed January 15, 2014.
24. Gaudet MM, Patel AV, Teras LR, et al. Obesity-related markers and breast cancer in CPS-II Nutrition Cohort. Int J Mol Epidemiol Genet. 2013;4(3):156-166.
25. Autier P, Koechlin A, Boniol M, et al. Serum insulin and C-peptide concentration and breast cancer: a meta-analysis. Cancer Causes Control. 2013;24(5):873-883.
26. Alschuler L, Kaczor T. Paper presented at: American Association of Naturopathic Physicians Annual Conference; July 10-13, 2013; Keystone, Colorado.
27. Gaudet MM, Patel AV, Teras LR, et al. Obesity-related markers and breast cancer in CPS-II Nutrition Cohort. Int J Mol Epidemiol Genet. 2013;4(3):156-166.
28. Oh SW, Park CY, Lee ES, et al. Adipokines, insulin resistance, metabolic syndrome, and breast cancer recurrence: a cohort study. Breast Cancer Res. 2011;13(2):R34.
29. Vuorinen-Markkola H, Yki-Järvinen H. Hyperuricemia and insulin resistance. J Clin Endocrinol Metab. 1994;78(1):25-29.
30. Renehan AG, Harvie M, Howell A. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and breast cancer risk: eight years on. Endocr Relat Cancer. 2006;13(2):273-278.
31. Key TJ, Appleby PN, Reeves GK, Roddam AW. Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol. 2010;11(6):530-542.
32. Minatoya M, Kutomi G, Asakura S, et al. Relationship of serum isoflavone, insulin and adiponectin levels with breast cancer risk. Breast Cancer. 2013;[Epub ahead of print].
33. Oh SW, Park CY, Lee ES, et al. Adipokines, insulin resistance, metabolic syndrome, and breast cancer recurrence: a cohort study. Breast Cancer Res. 2011;13(2):R34.
34. Physical activity and cancer. Cancer.gov website. http://www.cancer.gov/cancertopics/factsheet/prevention/physicalactivity. Accessed January 15, 2014.
35. Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. Physical activity and survival after breast cancer diagnosis. JAMA. 2005;293(20):2479-2486.
36. Wu Y, Zhang D, Kang S. Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2013;137(3):869-882.
37. Knowler WC, Barrett-connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.
38. Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374(9702):1677-1686.
39. Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care. 1994;17(1):30-36.
40. Henry RR, Gumbiner B. Benefits and limitations of very-low-calorie diet therapy in obese NIDDM. Diabetes Care. 1991;14(9):802-823.
41. Anderson JW, Allgood LD, Turner J, Oeltgen PR, Daggy BP. Effects of psyllium on glucose and serum lipid responses in men with type 2 diabetes and hypercholesterolemia. Am J Clin Nutr. 1999;70(4):466-473.
42. Giacco R, Parillo M, Rivellese AA, et al. Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients. Diabetes Care. 2000;23(10):1461-1466.
43. Chandalia M, Garg A, Lutjohann D, Von bergmann K, Grundy SM, Brinkley LJ. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med. 2000;342(19):1392-1398.
44. Chatsudthipong V, Muanprasat C. Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacol Ther. 2009;121(1):41-54.
45. Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metab Clin Exp. 2004;53(1):73-76.
46. Moller K, Krogh-Madsen R. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008;359(20):2170.
47. Rallidis LS, Lekakis J, Kolomvotsou A, et al. Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity. Am J Clin Nutr. 2009;90(2):263-268.
48. Liese AD, Nichols M, Sun X, D'agostino RB, Haffner SM. Adherence to the DASH Diet is inversely associated with incidence of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes Care. 2009;32(8):1434-1436.
49. Fung TT, Hu FB, Wu K, Chiuve SE, Fuchs CS, Giovannucci E. The Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets and colorectal cancer. Am J Clin Nutr. 2010;92(6):1429-1435.
50. Burke LE, Hudson AG, Warziski MT, et al. Effects of a vegetarian diet and treatment preference on biochemical and dietary variables in overweight and obese adults: a randomized clinical trial. Am J Clin Nutr. 2007;86(3):588-596.
51. Sluijs I, Beulens JW, Van der a DL, Spijkerman AM, Grobbee DE, Van der schouw YT. Dietary intake of total, animal, and vegetable protein and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study. Diabetes Care. 2010;33(1):43-48.
52. Harvie MN, Pegington M, Mattson MP, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes (Lond). 2011;35(5):714-727.
53. Partsalaki I, Karvela A, Spiliotis BE. Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents. J Pediatr Endocrinol Metab. 2012;25(7-8):697-704.
54. Martin J, Wang ZQ, Zhang XH, et al. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. Diabetes Care. 2006;29(8):1826-1832.
55. Racek J, Sindberg CD, Moesgaard S, et al. Effect of chromium-enriched yeast on fasting plasma glucose, glycated haemoglobin and serum lipid levels in patients with type 2 diabetes mellitus treated with insulin. Biol Trace Elem Res. 2013;155(1):1-4.
56. Marreiro DN, Geloneze B, Tambascia MA, Lerário AC, Halpern A, Cozzolino SM. Effect of zinc supplementation on serum leptin levels and insulin resistance of obese women. Biol Trace Elem Res. 2006;112(2):109-118.
57. Cohen N, Halberstam M, Shlimovich P, Chang CJ, Shamoon H, Rossetti L. Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1995;95(6):2501-2509.
58. Halberstam M, Cohen N, Shlimovich P, Rossetti L, Shamoon H. Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects. Diabetes. 1996;45(5):659-666.
59. Boden G, Chen X, Ruiz J, van Rossum GD, Turco S. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus. Metab Clin Exp. 1996;45(9):1130-1135.
60. Hruby A, Meigs JB, O'donnell CJ, Jacques PF, Mckeown NM. Higher magnesium intake reduces risk of impaired glucose and insulin metabolism and progression from prediabetes to diabetes in middle-aged americans. Diabetes Care. 2014;37(2):419-427.
61. Wang J, Persuitte G, Olendzki BC, et al. Dietary magnesium intake improves insulin resistance among non-diabetic individuals with metabolic syndrome participating in a dietary trial. Nutrients. 2013;5(10):3910-3919.
62. Mooren FC, Krüger K, Völker K, Golf SW, Wadepuhl M, Kraus A. Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial. Diabetes Obes Metab. 2011;13(3):281-284.
63. Santamaria A, Giordano D, Corrado F, et al. One-year effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome. Climacteric. 2012;15(5):490-495.
64. Capasso I, Esposito E, Maurea N, et al. Combination of inositol and alpha lipoic acid in metabolic syndrome-affected women: a randomized placebo-controlled trial. Trials. 2013;14:273.
65. Ansar H, Mazloom Z, Kazemi F, Hejazi N. Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients. Saudi Med J. 2011;32(6):584-588.
66. Khan H, Kunutsor S, Franco OH, Chowdhury R. Vitamin D, type 2 diabetes and other metabolic outcomes: a systematic review and meta-analysis of prospective studies. Proc Nutr Soc. 2013;72(1):89-97.
67. Mohr SB, Gorham ED, Alcaraz JE, et al. Serum 25-hydroxyvitamin D and prevention of breast cancer: pooled analysis. Anticancer Res. 2011;31(9):2939-2948.
68. Hodgson JM, Watts GF, Playford DA, Burke V, Croft KD. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr. 2002;56(11):1137-1142.
69. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(5 Suppl):1645S-1654S.
70. Banga A, Unal R, Tripathi P, et al. Adiponectin translation is increased by the PPARgamma agonists pioglitazone and omega-3 fatty acids. Am J Physiol Endocrinol Metab. 2009;296(3):E480-E489.
71. Derosa G, Maffioli P, Ferrari I, et al. Comparison between orlistat plus l-carnitine and orlistat alone on inflammation parameters in obese diabetic patients. Fundam Clin Pharmacol. 2011;25(5):642-651.
72. Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci. 2007;333(6):333-339.
73. MacDonald J. Blessed bitters. Herb Craft website. www.herbcraft.org/bitters.pdf. Accessed January 15, 2014.
74. Wei W, Zhao H, Wang A, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012;166(1):99-105.
75. Higdon JV, Frei B. Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr. 2003;43(1):89-143.
76. Basu A, Betts NM, Mulugeta A, Tong C, Newman E, Lyons TJ. Green tea supplementation increases glutathione and plasma antioxidant capacity in adults with the metabolic syndrome. Nutr Res. 2013;33(3):180-187.
77. Vieira senger AE, Schwanke CH, Gomes I, Valle gottlieb MG. Effect of green tea (Camellia sinensis) consumption on the components of metabolic syndrome in elderly. J Nutr Health Aging. 2012;16(9):738-742.
78. Preuss HG, Echard B, Fu J, et al. Fraction SX of maitake mushroom favorably influences blood glucose levels and blood pressure in streptozotocin-induced diabetic rats. J Med Food. 2012;15(10):901-908.
79. Lu T, Sheng H, Wu J, Cheng Y, Zhu J, Chen Y. Cinnamon extract improves fasting blood glucose and glycosylated hemoglobin level in Chinese patients with type 2 diabetes. Nutr Res. 2012;32(6):408-412.
80. Mang B, Wolters M, Schmitt B, et al. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipids in diabetes mellitus type 2. Eur J Clin Invest. 2006;36(5):340-344.
81. Khan A, Safdar M, Ali khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003;26(12):3215-3218.
82. Sethi J, Sood S, Seth S, Talwar A. Evaluation of hypoglycemic and antioxidant effect ofOcimum sanctum. Indian J Clin Biochem. 2004;19(2):152-155.
83. Gupta A, Gupta R, Lal B. Effect of Trigonella foenum-graecum (fenugreek) seeds on glycaemic control and insulin resistance in type 2 diabetes mellitus: a double blind placebo controlled study. J Assoc Physicians India. 2001;49:1057-6101.
84. Losso JN, Holliday DL, Finley JW, et al. Fenugreek bread: a treatment for diabetes mellitus. J Med Food. 2009;12(5):1046-1049.
85. Kumar SN, Mani UV, Mani I. An open label study on the supplementation of Gymnema sylvestre in type 2 diabetics. J Diet Suppl. 2010;7(3):273-282.
86. Bergner P. Insulin resistance: pathophysiology and natural therapeutics for metabolic syndrome. North American Institute of Medical Herbalism. 2006.
87. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92(12):994-1000.
88. Bower JE, Ganz PA, Aziz N. Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue. Psychosom Med. 2005;67(2):277-280.
89. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92(12):994-1000.
90. Lutgendorf SK, Weinrib AZ, Penedo F, et al. Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients. J Clin Oncol. 2008;26(29):4820-4827.
91. Hsiao FH, Jow GM, Kuo WH, et al. The effects of psychotherapy on psychological well-being and diurnal cortisol patterns in breast cancer survivors. Psychother Psychosom. 2012;81(3):173-182.
92. Phillips KM, Antoni MH, Lechner SC, et al. Stress management intervention reduces serum cortisol and increases relaxation during treatment for nonmetastatic breast cancer. Psychosom Med. 2008;70(9):1044-1049.
93. Holtcamp W. Obesogens: an environmental link to obesity. Environ Health Perspect. 2012;120(2):a62-a68.
94. The endocrine disruptor exchange (TEDX) list of potential endocrine disruptors. The Endocrine Disruption Exchange. http://endocrinedisruption.org/endocrine-disruption/tedx-list-of-potential-endocrine-disruptors/overview. Accessed January 15, 2014.
95. A patient handout on reducing risk of exposure to environmental toxins can be found at www.breastcancerfund.org/reduce-your-risk/tips/.
96. Clinicians working with breast cancer can also download the free publication “Body of Evidence: The Connection Between Breast Cancer and the Environment” at www.breastcancerfund.org/media/publications/state-of-the-evidence/.
97. Howdeshell KL, Peterman PH, Judy BM, et al. Bisphenol A is released from used polycarbonate animal cages into water at room temperature. Environ Health Perspect. 2003;111(9):1180-1187.
98. Trasande L, Attina TM, Blustein J. Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA. 2012;308(11):1113-1121.
99. Bhandari R, Xiao J, Shankar A. Urinary bisphenol A and obesity in U.S. children. Am J Epidemiol. 2013;177(11):1263-1270.
100. Sprague BL, Trentham-Dietz A, Hedman CJ, et al. Circulating serum xenoestrogens and mammographic breast density. Breast Cancer Res. 2013;15(3):R45.
101. Betancourt AM, Wang J, Jenkins S, Mobley J, Russo J, Lamartiniere CA. Altered carcinogenesis and proteome in mammary glands of rats after prepubertal exposures to the hormonally active chemicals bisphenol a and genistein. J Nutr. 2012;142(7):1382S-1388S.
102. Singh S, Li SS. Epigenetic effects of environmental chemicals bisphenol a and phthalates. Int J Mol Sci. 2012;13(8):10143-10153.
103. Dairkee SH, Luciani-torres MG, Moore DH, Goodson WH. Bisphenol-A-induced inactivation of the p53 axis underlying deregulation of proliferation kinetics, and cell death in non-malignant human breast epithelial cells. Carcinogenesis. 2013;34(3):703-712.
104. Lapensee EW, Lapensee CR, Fox S, Schwemberger S, Afton S, Ben-jonathan N. Bisphenol A and estradiol are equipotent in antagonizing cisplatin-induced cytotoxicity in breast cancer cells. Cancer Lett. 2010;290(2):167-173.
105. Lapensee EW, Tuttle TR, Fox SR, Ben-jonathan N. Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-alpha-positive and -negative breast cancer cells. Environ Health Perspect. 2009;117(2):175-180.
106. Zissu A. Obsogens: avoid chemicals linked to child obesity. Healthy Child website. http://healthychild.org/ what-are-obesogens-and-how-to-avoid-them/. Accessed January 15, 2014.
107. Bisphenol a (BPA). Breast Cancer Fund website. http://www.breastcancerfund.org/clear-science/radiation-chemicals-and-breast-cancer/bisphenol-a.html. Accessed January 3, 2014.
108. Thayer KA, Heindel JJ, Bucher JR, Gallo MA. Role of environmental chemicals in diabetes and obesity: a National Toxicology Program workshop review. Environ Health Perspect. 2012;120(6):779-789.
109. Braithwaite D, Izano M, Moore DH, et al. Smoking and survival after breast cancer diagnosis: a prospective observational study and systematic review. Breast Cancer Res Treat. 2012;136(2):521-533.
110. Thayer KA, Heindel JJ, Bucher JR, Gallo MA. Role of environmental chemicals in diabetes and obesity: a National Toxicology Program workshop review. Environ Health Perspect. 2012;120(6):779-789.
111. Kaur SD. The complete natural medicine guide to breast cancer, a practical manual for understanding, prevention & care. Toronto; R. Rose Inc; 2003.
112. Warner M, Eskenazi B, Mocarelli P, et al. Serum dioxin concentrations and breast cancer risk in the Seveso Women's Health Study. Environ Health Perspect. 2002;110(7):625-628.
113. Macon MB, Fenton SE. Endocrine disruptors and the breast: early life effects and later life disease. J Mammary Gland Biol Neoplasia. 2013;18(1):43-61.
114. Davis DL, Bradlow HL. Can environmental estrogens cause breast cancer?. Sci Am. 1995;273(4):167-172.
115. Thayer KA, Heindel JJ, Bucher JR, Gallo MA. Role of environmental chemicals in diabetes and obesity: a National Toxicology Program workshop review. Environ Health Perspect. 2012;120(6):779-789.
116. Carran M, Shaw IC. New Zealand Malayan war veterans' exposure to dibutylphthalate is associated with an increased incidence of cryptorchidism, hypospadias and breast cancer in their children. N Z Med J. 2012;125(1358):52-63.
117. López-carrillo L, Hernández-ramírez RU, Calafat AM, et al. Exposure to phthalates and breast cancer risk in northern Mexico. Environ Health Perspect. 2010;118(4):539-544.
118. Mitka M. Rigorous evidence slim for determining health risks from natural gas fracking. JAMA. 2012;307(20):2135-2136.
119. Waxman HA, Markey EJ, DeGette D. Chemicals used in hydraulic fracturing. United States House of Representatives Committee on Energy and Commerce Minority Staff. April 2011. http://democrats.energycommerce.house.gov/sites/default/files/documents/Hydraulic-Fracturing-Chemicals-2011-4-18.pdf. Accessed January 15, 2014.
120. Anderson LN, Cotterchio M, Vieth R, Knight JA. Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. Am J Clin Nutr. 2010;91(6):1699-1707.
121. Khan QJ, Reddy PS, Kimler BF, et al. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat. 2010;119(1):111-118.
122. Brasky TM, Lampe JW, Potter JD, Patterson RE, White E. Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev. 2010;19(7):1696-1708.
123. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99(6A):35C-43C.
124. Elia M, van Bokhorst-de van der Schueren MA, Garvey J, et al. Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: a systematic review. Int J Oncol. 2006;28(1):5-23.
125. Bougnoux P, Hajjaji N, Maheo K, Couet C, Chevalier S. Fatty acids and breast cancer: sensitization to treatments and prevention of metastatic re-growth. Prog Lipid Res. 2010;49(1):76-86.
126. Bougnoux P, Hajjaji N, Ferrasson MN, Giraudeau B, Couet C, Le floch O. Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial. Br J Cancer. 2009;101(12):1978-1985.
127. Bonatto SJ, Oliveira HH, Nunes EA, et al. Fish oil supplementation improves neutrophil function during cancer chemotherapy. Lipids. 2012;47(4):383-390.
128. Bagga D, Capone S, Wang HJ, et al. Dietary modulation of omega-3/omega-6 polyunsaturated fatty acid ratios in patients with breast cancer. J Natl Cancer Inst. 1997;89(15):1123-1131.
129. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007;129(1-2):210-223.
130. Patterson RE, Flatt SW, Newman VA, et al. Marine fatty acid intake is associated with breast cancer prognosis. J Nutr. 2011;141(2):201-6.
131. Conklin KA. Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity. Integr Cancer Ther. 2005;4(2):110-130.
132. Sachdanandam P. Antiangiogenic and hypolipidemic activity of coenzyme Q10 supplementation to breast cancer patients undergoing Tamoxifen therapy. Biofactors. 2008;32(1-4):151-159.
133. Hershman DL, Unger JM, Crew KD, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol. 2013;31(20):2627-2633.
134. Kimura Y, Ito H, Hatano T. Effects of mace and nutmeg on human cytochrome P450 3A4 and 2C9 activity. Biol Pharm Bull. 2010;33(12):1977-1982.
135. Kimura Y, Ibid.
136. Wang J, Liu Q, Yang Q. Radiosensitization effects of berberine on human breast cancer cells. Int J Mol Med. 2012;30(5):1166-1172.
137. Li GH, Wang DL, Hu YD, et al. Berberine inhibits acute radiation intestinal syndrome in human with abdomen radiotherapy. Med Oncol. 2010;27(3):919-925.
138. Patil D, Gautam M, Gairola S, Jadhav S, Patwardhan B. Effect of Botanical Immunomodulators on Human CYP3A4 Inhibition: Implications for Concurrent Use as Adjuvants in Cancer Therapy. Integr Cancer Ther. 2013;[Epub ahead of print].
139. Patil D, Gautam M, Gairola S, Jadhav S, Patwardhan B. Effect of Botanical Immunomodulators on Human CYP3A4 Inhibition: Implications for Concurrent Use as Adjuvants in Cancer Therapy. Integr Cancer Ther. 2013;[Epub ahead of print].
140. Liu J, He C, Zhou K, Wang J, Kang JX. Coptis extracts enhance the anticancer effect of estrogen receptor antagonists on human breast cancer cells. Biochem Biophys Res Commun. 2009;378(2):174-178.
141. Sun CL, Yuan JM, Koh WP, Yu MC. Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies. Carcinogenesis. 2006;27(7):1310-1315.
142. Chen XQ, Wang XB, Guan RF, et al. Blood anticoagulation and antiplatelet activity of green tea (-)-epigallocatechin (EGC) in mice. Food Funct. 2013;4(10):1521-1525.
143. Zhang G, Wang Y, Zhang Y, et al. Anti-cancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy. Curr Mol Med. 2012;12(2):163-176.
144. Mooiman KD, Maas-Bakker RF, Hendrikx JJ, et al. The effect of complementary and alternative medicines on CYP3A4-mediated metabolism of three different substrates: 7-benzyloxy-4-trifluoromethyl-coumarin, midazolam and docetaxel. J Pharm Pharmacol. 2014;[Epub ahead of print].
145. Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta. 2002;1542(1-3):149-159.
146. Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol. 2004;56(10):1307-1314.
147. Lecumberri E, Dupertuis YM, Miralbell R, Pichard C. Green tea polyphenol epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy. Clin Nutr. 2013;32(6):894-903.
148. Donovan JL, Chavin KD, Devane CL, et al. Green tea (Camellia sinensis) extract does not alter cytochrome p450 3A4 or 2D6 activity in healthy volunteers. Drug Metab Dispos. 2004;32(9):906-908.
149. Engdal S, Nilsen OG. In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients. Phytother Res. 2009;23(7):906-912.
150. Sakata M, Ikeda T, Imoto S, Jinno H, Kitagawa Y. Prevention of mammary carcinogenesis in C3H/OuJ mice by green tea and tamoxifen. Asian Pac J Cancer Prev. 2011;12(2):567-571.
151. Sartippour MR, Pietras R, Marquez-garban DC, et al. The combination of green tea and tamoxifen is effective against breast cancer. Carcinogenesis. 2006;27(12):2424-2433.