Understanding Diet & Lifestyle Risk Factors in Breast Cancer

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The various risk factors that could be responsible for the development of breast cancer in women including ethnicity, age, obesity, pregnancy, genetic mutation and estrogen metabolism, were discussed thoroughly in the previous article “Breast Cancer”.  

The possibility that environmental exposures and lifestyle choices may actually play decisive, influential roles in the pathogenesis of breast cancer warrants further exploration. 

A marked sixfold difference in breast cancer incidence between Asia and the West has been well documented since the mid-1960’s.  However, this gap has been observed to be narrowing dramatically.  Breast cancer has now become the most common cancer among women in China, having increased at a rate of 3.5% per annum from 2000 to 2013.  Notably, urban areas with higher population density also showed higher breast cancer rates compared to rural areas.

This finding supports the evidence from another study that tracked breast cancer development in women who migrated to the United States from China.  The women who migrated to the United States developed cancer at rates doubling those who lived in Tianjin and Shanghai, the two largest cities in China.  Chinese Americans born in the United States develop breast cancer at levels similar to White women.  Third generation Chinese Americans have higher incidences in breast cancer development than White females in the USA. 

Diet & Lifestyle Affects Breast Cancer Risks

Diet and lifestyle changes in women living in modern China and women who either migrated to the United States or were born there may cause epigenetic changes in their genome that can alter estrogen metabolism or gene expressions.  These epigenetic changes may have contributed to the significant elevation in breast cancer incidence, obliterating the previously observed differences between various ethnicities. 

The traditional Chinese diet includes rice; wheat and wheat products; vegetables; and is low in fats and animal-source foods.  As a result of the rapid economic development in China, the structure of the Chinese diet has been shifting away from traditional high carbohydrate, high fiber diets toward high-fat, energy-dense, low-carbohydrate and low-fiber diets that are similar to standard American diets characterized by high intakes of red meat, processed meat, pre-packaged foods, fried foods, high-fat dairy products, and high-sugar drinks.

Daily Intake of Animal Source Foods in China (grams/day), 1991–2011

[Source: Fengying Zhai, Shufa Du, Zhihong Wang, Jiguo Zhang, Wenwen Du, and Barry Popkin Dynamics of the Chinese Diet and the Role of Urbanicity, 1991– 2011 Obes Rev. 2014 January ; 15(0 1): . doi:10.1111/obr.12124.]

 

This remarkable shift in diet patterns also produced a dramatic change in disease patterns in China.  The high prevalence of malnutrition and nutritional deficiency in the past is now replaced by diet-related non-communicable diseases such as obesity, diabetes, cardiovascular disease and cancer.  Cancer has now become the leading cause of death in China. Breast cancer in Chinese women represented 19.2% of all total cases diagnosed in females in 2018, compared to 23.8%  in the United States. 

The role of diet has long been implicated in breast cancer development.  Modifications in lifestyle can also alter outcomes in breast cancer treatments.  A meta-analysis of 14 cohort studies showed that women with the highest levels of total fat intake had a 13% increase in risks for developing breast cancer.  Among the various types of fats, intake of saturated fat has been shown to be positively related with breast cancer risks

The association between the shift of diet patterns in women who emigrated and the corresponding increase in breast cancer incidence strongly supports the belief by experts that lifestyle and diet patterns can influence cancer development or even lower mortality after diagnosis of breast cancer across all ethnicity. 

Low-fat Diet and Breast Cancer Mortality in the United States

In July 2019, an astounding report released by the American Institute for Cancer Research indicated that mortality risk after breast cancer diagnosis can be reduced up to 21% by following a balanced diet that is low in fats while including daily servings of vegetables, fruits and whole grains, compared to a normal diet that is higher in fat and animal products. The findings of this report was based on the first ever large randomized clinical trial conducted across 40 US clinical centers involving a total of 48,835 postmenopausal women between the ages of 50 to 79 years with no previous breast cancer and all had dietary fat intake of more than 32%.  

From 1993 to 1998, participants were randomly placed into a dietary intervention group that reduced fat intake to no more than 20% of energy while increasing vegetables, fruits and grain intake, or a normal diet control group.  The results from 17.7 years of follow-up showed that during the intervention period, of the 1,764 women diagnosed with breast cancer, and 516 total deaths, the overall survival rate was significantly better for women in the low-fat intervention group than in the normal diet comparison group. 

[Source: Rowan T. Chlebowski et al. JAMA Oncol. 2018 Oct; 4(10): e181212.doi: 10.1001/jamaoncol.2018.1212: 10.1001/jamaoncol.2018.1212 Association of Low-Fat Dietary Pattern With Breast Cancer Overall Survival]

For all the women who received a diagnosis of breast cancer during the dietary intervention period, those in the dietary group had increased overall survival. The authors of the trial believed that the enhanced survival could be due to better survival from several causes of death. The findings from this study provided reliable evidence that dietary change can reduce a postmenopausal woman’s risk of dying from breast cancer. 

Physical Activities Reduce Breast Cancer Risk & Mortality

Recreational physical activity is associated with reduced cancer risk. An analysis of 73 studies collected around the world revealed that physically active women had a 25% average risk reduction in breast cancer compared to the least active women. Activities that were moderate to vigorous; performed regularly; sustained over the lifetime or initiated after menopause all exhibited strong correlations to reduced breast cancer risk. 

Epidemiological evidence gathered from various studies confirmed that physical activity performed by breast cancer survivors significantly lowered breast cancer mortality risk while improving physiological and immune functions. Some studies even showed adaptations to physical activity in metabolic biomarkers including insulin and insulin-like growth factors. Estrogen levels, which are usually elevated in breast cancer, were also found to be suppressed by physical activity. 

Alcohol Intake Modulates Breast Cancer Risks

The use of alcohol is now recognized to be a leading risk factor for death and disability.  An extensive, comprehensive meta-analysis that used data sources from 694 individual and population-level alcohol consumption together with 592 prospective and retrospective studies on the risk of alcohol use produced the findings that in 2016, alcohol use was the 7th leading risk factor for both deaths and DALYs (disability-adjusted life year, expressed as the number of years lost due to ill-health, disability or early death).

Alcoholic beverages is classified by the International Agency for Research on Cancer (IARC) as a Group 1 human carcinogen capable of inducing female breast cancer, as well as colorectum, larynx, liver, esophagus, oral cavity, and pharynx cancers.  Alcohol has been found to be attributable to 6.4% of breast cancer cases in the United Kingdom.  A meta-analysis based on 53 epidemiological studies collected worldwide, indicated that an intake of 35-44 grams of alcohol per day can increase the risk of breast cancer by 32%, with a 7.1% increase in the relative risk for each additional 10 grams of alcohol per day.  

The metabolism of ethanol involves both microsomal and mitochondrial systems that may produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). Excessive ROS creates uncontrolled oxidative stress that will damage biomolecules and DNA. 

The consumption of red or processed meat together with alcohol has been shown to produce a cascade of metabolic reactions that significantly increase oxidative stress and genotoxicity in MCF-7 breast cancer cells. The micro-environment of breast cancer cells highly favor increased oxidative stress. Under oxidative stress, the tumor stroma releases high energy nutrients that support cancer cell growth and survival. 

Diets that are high in calories, rich in processed meats, fats and carbohydrates can easily result in the generation of oxidative stress and the release of pro-inflammatory cytokines.  Oxidative stress is one of the most important causes for breast cancer. 

Estrogen & Oxidative Stress in Breast Cancer

Due to the effects of oxidative stress on estrogen metabolism and epigenetic modulation, oxidative stress is now regarded as one of the major contributing factors associated with breast cancer development, progression and treatment outcome.

Estrogen production in women has been linked to increased risk of breast cancer. The conversion of estradiol to genotoxic metabolites in breast tissue initiates the formation of estrogen-DNA adducts, causing DNA mutations that leads to tumorigenesis. It is now believed that oxidative stress may be the trigger for this cascade of effects in breast cancer proliferation. 

Hamsters treated with either chemicals that generate oxidative stress or a potent estrogen without the ability to produce oxidative metabolites did not cause tumorigenesis.  However, when estrogen and oxidative stress inducing chemicals were administered together, they were able to induce renal tumors.  

Heightened economic development together with accelerating urbanization that is characterized by the adoption of Westernized lifestyles may have contributed greatly to the overall increase in breast cancer prevalence in China. A western diet and lifestyle is believed to be conducive to the generation of higher levels of oxidative stress that could result in inflammatory metabolic diseases including cancer.

Since the 1990s, breast cancer incidence in China has increased at more than double the incidence rates reported worldwide. Geographical variation in breast cancer mortality rates has also increased significantly over time at the regional level.  

A survey of 31 provinces in China demonstrated that the overall age-standardized mortality rate (ASMR) for breast cancer increased from  2.98 per 100,000 in 1973–1975 to to 3.85 per 100,000 in 2004–2005.  Tibet and Qinghai provinces had the lowest ASMR rates of 1.00 to 1.49 per 100,000 in 1973-1975.  But by 2004-2005, the ASMR rate had doubled in Tibet, whereas Qinghai showed quadrupled ASMR rates for breast cancer.

Female Breast Cancer Age-standardized Mortality Rates (ASMRs) by province in China in 1973-1975 

[Source: Changfa Xia, Clare Kahn, Jinfeng Wang, Yilan Liao, Wanqing Chen, and Xue Qin Yu  Temporal Trends in Geographical Variation in Breast Cancer Mortality in China, 1973–2005: An Analysis of Nationwide Surveys on Cause of Death Int J Environ Res Public Health. 2016 Oct; 13(10): 963. doi: 10.3390/ijerph13100963]

 

Female Breast Cancer Age-standardized Mortality Rates (ASMRs) by province in China in 2004-2005 

[Source: Changfa Xia, Clare Kahn, Jinfeng Wang, Yilan Liao, Wanqing Chen, and Xue Qin Yu  Temporal Trends in Geographical Variation in Breast Cancer Mortality in China, 1973–2005: An Analysis of Nationwide Surveys on Cause of Death Int J Environ Res Public Health. 2016 Oct; 13(10): 963. doi: 10.3390/ijerph13100963]

 

Artificial Light At Night (ALAN) – Significant Source of Cancer on a Global Level

It would be difficult to imagine that dietary changes  could be the sole driver behind increased breast cancer prevalence and mortality rates.  Many experts believe that exposure to light at night may increase cancer risks, especially in cancers that are affected by hormones, such as breast and prostate cancers. 

Women who work night shifts have shown to be at higher risk for developing breast cancer.  Women living in the highest light at night (LAN) exposed countries have a 30-50% higher risk in developing breast cancer than women in the lowest LAN exposed countries. 

An extensive evaluation of ecological data collected from 158 countries around the world in 2015 that measured age-standardized rates of cancer against exposure to artificial light at night (ALAN), discovered that ALAN leads to cancer causation in humans.

After adjusting for population sizes; particulate matters that may cause air pollution; electricity consumption at national levels; as well as land areas covered by forests, the authors of the study found that the age-standardized rates of all forms of cancer, but particularly the most common lung, breast, colorectal and prostate cancers were SIGNIFICANTLY POSITIVELY associated with light exposure at night in all 158 countries studied

An impressive study published by Harvard University in 2017 found that women who lived in neighborhoods with higher levels of residential outdoor light at night suffered greater incidence of breast cancer.  From 1989 to 2013, researchers followed 109,672 women, identifying 3,549 breast cancer cases over the 2,187,425 person-years. They also observed a strong positive correlation between breast cancer risk and cumulative average exposure to residential outdoor light at night.  However, the relationship between outdoor light at night and invasive breast cancer risk was confined only to current and past premenopausal smokers, as well as women who worked night shifts

Smoking has been associated with breast cancer development in some studies, but not others.  Compared to never smokers, women who smoked more than 15 pack-years were found with significantly lower levels of melatonin. Lower melatonin is strongly associated with increased breast cancer risks

Light At Night Suppresses Melatonin 

Exposure to light at night has been demonstrated to disrupt circadian rhythm and suppress melatonin production.

Melatonin is known as the “hormone of darkness” as it is produced by the pineal gland in the absence of light. The synthesis of melatonin in the pineal gland has been found to be inhibited by light.  Melatonin has been found to exert oncostatic effects, inhibiting the growth of breast cancer cells by exerting both cytotoxic and anti-proliferative effects via a variety of mechanisms

The dysregulation of melatonin signaling at night is part of the general phenomenon of systemic circadian disruptions as a result of exposure to light at night.  All life forms on earth have evolved with the 24 hour light/dark cycle of sunrise and sunset. The circadian rhythmicity of life forms are the daily oscillations of complex physiological processes that regulate anticipatory modulations that respond to changes in the environment.

Disruption of circadian rhythms inevitably leads to alterations in circadian gene behavior in a way that impacts disease progression.  It has been estimated that as much as 2–10% of all mammalian genes are clock-controlled.  Many core circadian genes have been identified and demonstrated to play major roles in numerous cancer related biological pathways including cell-cycle regulation, DNA repair and apoptosisExposure to white light at night not only extinguishes the cancer inhibitory effects of melatonin, but can intensify tumor growth rates in a dose dependent manner

Increased risk of breast cancer has been associated with deviations in protein expressions in circadian genes such as PER 1, 2 and 3. In estrogen receptor-positive and progesterone receptor-positive (ER+/PR+) breast cancer tissues, PER1 is found to be significantly hypomethylated. DNA methylation is an epigenetic mechanism where the addition of a methyl group to the DNA can modify the function and affect protein expressions without altering the actual DNA sequence. 

A cross-sectional study in Poland involving nurses and midwives working rotating shifts found an association between lower methylation of the PER2 gene and higher monthly frequency of night duties.  Scientists also found lower status of PER1 methylation in women with longer lifetime duration of shift work compared to women with up to 10 years of rotating shift work. 

A comparison between the areas in the diagram below showing the highest levels of  change in brightness at night in China between 1992-1996 and 2008-2012 with the areas showing the highest age-standardized breast cancer mortality rates rates in China during 2004-2005 can easily demonstrate the validity of the theory of the influence of light at night on breast cancer development. 

 Change in Brightness at Night in China between 1992–1996 and 2008–2012

[Source: Pengpeng Han, Jinliang Huang, Rendong Li, Lihui Wang, Yanxia Hu, Jiuling Wang and Wei Huang  Monitoring Trends in Light Pollution in China Based on Nighttime Satellite Imagery Remote Sens. 2014, 6, 5541-5558; doi:10.3390/rs6065541]

 

Lifestyle modifications including diet, alcohol intake, smoking, physical activity and exposure to artificial light at night (ALAN) can all contribute to factors that may increase or reduce breast cancer risk as well as breast cancer mortality after diagnosis.  Compared to other risk factors in breast cancer, such as ethnicity, age, obesity, pregnancy, genetic mutation and estrogen metabolism that may not be easily changed, lifestyle modifications are important breast cancer risk factors that can be controlled and changed. 

The inclusion of natural products that inhibit aromatase may also be an effective means to decrease estrogen production in postmenopausal women to reduce breast cancer risks.  Aromatase is the enzyme that converts the androgen hormone into estrogen in the body. Although the use of synthetic aromatase inhibitors (AIs) has produced successful clinical results in the treatment of postmenopausal estrogen receptor-positive breast cancer, the use of synthetic AIs to curb estrogen production may produce unwanted side effects including osteoporosis, cardiovascular dysfunctions and cognitive declines. Therefore, employing natural products that could inhibit aromatase may be a better option with reduced side effects.

Of the many natural products evaluated for their ability to inhibit aromatase, flavonoids including apigenin, chrysin and naringenin have been found to be the most active in aromatase inhibition. Even though resveratrol, the stilbenoid found in red wine has been reported to exert strong aromatase inhibition in vitro, the results could not be replicated by others.

Being physically active; observing a balanced nutritious diet that is low in fat; avoiding exogenous elements that can generate excessive oxidative stress such as environmental pollutants/toxins, alcohol and cigarette smoke; and reducing artificial light at night remain as some of the most achievable and effective means to lower breast cancer incidence and mortality. 

 

 

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