Obesity and Triple-Negative Breast Cancer
2017; Elsevier BV; Volume: 188; Issue: 2 Linguagem: Inglês
10.1016/j.ajpath.2017.09.018
ISSN1525-2191
AutoresEric C. Dietze, Tanya Chavez, Victoria L. Seewaldt,
Tópico(s)Nutritional Studies and Diet
ResumoOnce considered a problem of Western nations, obesity (body mass index ≥30 kg/m2) has rapidly increased since the 1970s to become a major threat to world health. Since 1970, the face of obesity has changed from a disease of affluence and abundance to a disease of poverty. During the last 10 years, studies have mechanistically linked obesity and an obese tumor microenvironment with signaling pathways that predict aggressive breast cancer biology. For example, in the United States, African American women are more likely than non-Hispanic European American women to be obese and to be diagnosed with triple-negative breast cancer (TNBC). In 2008, the Carolina Breast Study found that obesity (increased waist/hip ratio) was linked to an increased incidence of TNBC in premenopausal and postmenopausal African American women. Subsequently, several groups have investigated the potential link between obesity and TNBC in African American women. To date, the data are complex and sometimes contradictory. We review epidemiologic studies that investigated the potential association among obesity, metabolic syndrome, and TNBC in African American women and mechanistic studies that link insulin signaling to the obese breast microenvironment, tissue inflammation, and aggressive TNBC biology. Once considered a problem of Western nations, obesity (body mass index ≥30 kg/m2) has rapidly increased since the 1970s to become a major threat to world health. Since 1970, the face of obesity has changed from a disease of affluence and abundance to a disease of poverty. During the last 10 years, studies have mechanistically linked obesity and an obese tumor microenvironment with signaling pathways that predict aggressive breast cancer biology. For example, in the United States, African American women are more likely than non-Hispanic European American women to be obese and to be diagnosed with triple-negative breast cancer (TNBC). In 2008, the Carolina Breast Study found that obesity (increased waist/hip ratio) was linked to an increased incidence of TNBC in premenopausal and postmenopausal African American women. Subsequently, several groups have investigated the potential link between obesity and TNBC in African American women. To date, the data are complex and sometimes contradictory. We review epidemiologic studies that investigated the potential association among obesity, metabolic syndrome, and TNBC in African American women and mechanistic studies that link insulin signaling to the obese breast microenvironment, tissue inflammation, and aggressive TNBC biology. During the past 20 years, the United States, as well as much of the world, has experienced an increasing obesity epidemic. The obesity epidemic has disproportionately affected the poor. Once a disease of the wealthy, obesity is now a disease of poverty. Possible contributors include disparities in income that promote consumption of inexpensive high-calorie foods with low nutritional value,1Hawkes C. Uneven dietary development: linking the policies and processes of globalization with the nutrition transition, obesity and diet-related chronic diseases.Global Health. 2006; 2: 4Crossref PubMed Scopus (546) Google Scholar disparities in access to healthy food sources (food deserts),2Cummins S. Macintyre S. “Food deserts” - evidence and assumption in health policy making.BMJ. 2002; 325: 436-438Crossref PubMed Scopus (356) Google Scholar and lack of exercise. The obesity epidemic has also disproportionately affected women of African descent. For example, in the United States, >58.6% of African American women are obese (versus 34.5% non-Hispanic European Americans).3Bernstein L. Teal C.R. Joslyn S. Wilson J. Ethnicity-related variation in breast cancer risk factors.Cancer. 2003; 97: 222-229Crossref PubMed Scopus (85) Google Scholar, 4Kim S.Y. Dietz P.M. England L. Morrow B. Callaghan W.M. Trends in pre-pregnancy obesity in nine states, 1993–2003.Obesity. 2007; 15: 986-993Crossref PubMed Scopus (342) Google Scholar For reasons discussed in this review, these women are also more likely to develop triple-negative breast cancers (TNBCs). TNBCs lack expression of estrogen receptor (ER) and progesterone receptor (PR) and do not overexpress tyrosine kinase human epidermal growth factor receptor 2.5Foulkes W.D. Smith I.E. Reis-Filho J.S. Triple-negative breast cancer.N Engl J Med. 2010; 363: 1938-1948Crossref PubMed Scopus (2713) Google Scholar, 6Sorlie T. Perou C.M. Tibshirani R. Aas T. Geisler S. Johnsen H. Hastie T. Eisen M.B. van de Rijn M. Jeffrey S.S. Thorsen T. Quist H. Matese J.C. Brown P.O. Botstein D. Lonning P.E. Borresen-Dale A.L. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.Proc Natl Acad Sci U S A. 2001; 98: 10869-10874Crossref PubMed Scopus (8538) Google Scholar The basal subset of TNBC is characterized by expression of basal-type cytokeratin 5 and cytokeratin 6 and high expression of epidermal growth factor receptor, and frequently exhibits aggressive clinical behavior.6Sorlie T. Perou C.M. Tibshirani R. Aas T. Geisler S. Johnsen H. Hastie T. Eisen M.B. van de Rijn M. Jeffrey S.S. Thorsen T. Quist H. Matese J.C. Brown P.O. Botstein D. Lonning P.E. Borresen-Dale A.L. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.Proc Natl Acad Sci U S A. 2001; 98: 10869-10874Crossref PubMed Scopus (8538) Google Scholar TNBCs most frequently occur in women with germline BRCA1 mutations and in premenopausal women of African descent.7Dietze E.C. Sistrunk C. Miranda-Carboni G. O'Regan R. Seewaldt V.L. Triple-negative breast cancer in African-American women: disparities versus biology.Nat Rev Cancer. 2015; 15: 248-254Crossref PubMed Scopus (261) Google Scholar The Carolina Breast Study found an association between obesity, as measured by increased waist/hip ratio (WHR), and an increased incidence of TNBC in premenopausal and postmenopausal African American women. Subsequently, a number of groups have investigated the potential link between obesity and TNBC in African American women. However, to date, studies have relied on body shape rather than biology; the data are complex and sometimes contradictory. Nevertheless, the past 10 years has witnessed a substantial increase in our understanding of both the biology of aggressive TNBC and the importance of the breast microenvironment on aggressive cancer biology. Key drivers of TNBC include i) genomic instability, including loss of p53 function8Lehmann B.D. Pietenpol J.A. 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Adipose microenvironment promotes triple negative breast cancer cell invasiveness and dissemination by producing CCL5.Oncotarget. 2016; 7: 24495-24509Crossref PubMed Scopus (86) Google Scholar We review epidemiologic studies that investigated the potential association among obesity, metabolic syndrome, and TNBC in African American women and mechanistic studies that link insulin signaling, the obese breast microenvironment, and inflammation with aggressive TNBC biology. The Centers for Disease Control and Prevention (CDC) defines a body mass index (BMI) ≥30 kg/m2 as obesity or metabolically unhealthy (CDC, https://www.cdc.gov/obesity/adult/defining.html, last accessed April 3, 2017). Abdominal obesity, as measured by WHR or by waist circumference, is another commonly used measure of obesity or poor metabolic health (metabolically unhealthy). Women with a WHR of ≥0.85 are considered to be at substantially increased risk for metabolic complications by the World Health Organization.20WHOWaist Circumference and Waist-Hip Ratio: Report of a WHO Expert Consultation. World Health Organization, Geneva, Switzerland2011Google Scholar The CDC considers a waist circumference of ≥88 cm metabolically unhealthy. Although overall obesity is associated with many adverse health outcomes, abdominal obesity may have an even greater adverse effect on metabolic health [heart disease, insulin resistance (prediabetes), type 2 diabetes] and cancer. In 2014, the National Health and Nutrition Examination Surveys reported that in the United States, 35.0% of adult men and 40.4% of adult women were obese as measured by BMI.21Flegal K.M. Kruszon-Moran D. Carroll M.D. Fryar C.D. Ogden C.L. Trends in obesity among adults in the United States, 2005 to 2014.JAMA. 2016; 315: 2284-2291Crossref PubMed Scopus (2048) Google Scholar, 22Seidell J.C. 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Obesity: the obesity epidemic in the USA - no end in sight?.Nat Rev Endocrinol. 2016; 12: 499-500Crossref PubMed Scopus (26) Google Scholar Similarly, obesity has steadily increased in adolescents 12 to 19 years of age. In particular, severe obesity increased in adolescents from 2.6% in 1988 to 1994 to 9.1% in 2013 to 2014.21Flegal K.M. Kruszon-Moran D. Carroll M.D. Fryar C.D. Ogden C.L. Trends in obesity among adults in the United States, 2005 to 2014.JAMA. 2016; 315: 2284-2291Crossref PubMed Scopus (2048) Google Scholar, 22Seidell J.C. Halberstadt J. Obesity: the obesity epidemic in the USA - no end in sight?.Nat Rev Endocrinol. 2016; 12: 499-500Crossref PubMed Scopus (26) Google Scholar, 23Ogden C.L. Carroll M.D. Lawman H.G. Fryar C.D. Kruszon-Moran D. Kit B.K. Flegal K.M. Trends in obesity prevalence among children and adolescents in the United States, 1988-1994 through 2013-2014.JAMA. 2016; 315: 2292-2299Crossref PubMed Scopus (1632) Google Scholar These studies highlight that in the United States obesity is increasing in women and adolescents and remains a pressing public health challenge. Before the 1970s, obesity was associated with wealth and nutrition.21Flegal K.M. Kruszon-Moran D. Carroll M.D. Fryar C.D. Ogden C.L. Trends in obesity among adults in the United States, 2005 to 2014.JAMA. 2016; 315: 2284-2291Crossref PubMed Scopus (2048) Google Scholar, 22Seidell J.C. Halberstadt J. Obesity: the obesity epidemic in the USA - no end in sight?.Nat Rev Endocrinol. 2016; 12: 499-500Crossref PubMed Scopus (26) Google Scholar, 24Ogden C.L. Carroll M.D. Kit B.K. Flegal K.M. Prevalence of childhood and adult obesity in the United States, 2011-2012.JAMA. 2014; 311: 806-814Crossref PubMed Scopus (6302) Google Scholar, 25Malik V.S. Willett W.C. Hu F.B. Global obesity: trends, risk factors and policy implications.Nat Rev Endocrinol. 2013; 9: 13-27Crossref PubMed Scopus (870) Google Scholar Today, it is common to find obesity to be associated with poverty and malnutrition.25Malik V.S. Willett W.C. Hu F.B. Global obesity: trends, risk factors and policy implications.Nat Rev Endocrinol. 2013; 9: 13-27Crossref PubMed Scopus (870) Google Scholar The reason for this shift is not well understood and is likely multifactorial.25Malik V.S. Willett W.C. Hu F.B. Global obesity: trends, risk factors and policy implications.Nat Rev Endocrinol. 2013; 9: 13-27Crossref PubMed Scopus (870) Google Scholar, 26Finucane M.M. Stevens G.A. Cowan M.J. Danaei G. Lin J.K. Paciorek C.J. Singh G.M. Gutierrez H.R. Lu Y.A. Bahalim A.N. Farzadfar F. Riley L.M. Ezzati M. Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index)National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants.Lancet. 2011; 377: 557-567Abstract Full Text Full Text PDF PubMed Scopus (3128) Google Scholar Possible contributors include socioeconomic factors that promote consumption of inexpensive high-calorie foods with low nutritional value1Hawkes C. Uneven dietary development: linking the policies and processes of globalization with the nutrition transition, obesity and diet-related chronic diseases.Global Health. 2006; 2: 4Crossref PubMed Scopus (546) Google Scholar and disparities in access to healthy food sources (ie, food deserts).2Cummins S. Macintyre S. “Food deserts” - evidence and assumption in health policy making.BMJ. 2002; 325: 436-438Crossref PubMed Scopus (356) Google Scholar, 27Whitacre P.T. Tsai P. Mulligan J. The Public Health Effects of Food Deserts: Workshop Summary. The National Academies Press, Washington, DC2009Google Scholar Throughout the world, obesity is more prevalent in urban areas and in individuals with less education and income.24Ogden C.L. Carroll M.D. Kit B.K. Flegal K.M. Prevalence of childhood and adult obesity in the United States, 2011-2012.JAMA. 2014; 311: 806-814Crossref PubMed Scopus (6302) Google Scholar, 25Malik V.S. Willett W.C. Hu F.B. Global obesity: trends, risk factors and policy implications.Nat Rev Endocrinol. 2013; 9: 13-27Crossref PubMed Scopus (870) Google Scholar Compared with the poor, affluent individuals have additional income to purchase healthy foods, adequate time for leisure and physical activities, and access to quality health care.28Caballero B. A nutrition paradox - underweight and obesity in developing countries.N Engl J Med. 2005; 352: 1514-1516Crossref PubMed Scopus (288) Google Scholar In contrast, poor households may lack access to healthy foods, which has the potential to exacerbate poverty by trapping the poor in a cycle of obesity and obesity-associated health problems, further increasing economic and health disparities.29Cummins S. Macintyre S. Food environments and obesity - neighbourhood or nation?.Int J Epidemiol. 2006; 35: 100-104Crossref PubMed Scopus (511) Google Scholar There is a strong correlation between poverty and obesity. Until approximately 40 years ago, calories were associated with nutrition. With the advent of junk food and fast food, the opposite has become true. Less nutritious, calorie-dense foods are often less expensive than healthier foods; as a result, poor families often eat high-calorie food with low nutritional content (Trust for America's Health, http://healthyamericans.org/report/108, last accessed April 3, 2017). Disparities in income have a particular effect on African Americans. For the past 30 years, African American families have earned $1 for every $2 earned by non-Hispanic European American families (Urban Institute, http://www.urban.org/research/publication/less-equal-racial-disparities-wealth-accumulation, last accessed April 3, 2017). In addition, >30% of African American families with children live below the poverty line (US Census Bureau, https://www.census.gov/content/dam/Census/library/publications/2017/demo/P60-259.pdf, last accessed April 3, 2017), and 12% of African American families live in deep poverty (<50% of the US federal poverty threshold) (US Census Bureau, https://www.census.gov/library/publications/2013/demo/p60-245.html, last accessed April 3, 2017). In African American families, 22.5% do not have consistent access to adequate food because of lack of money or other resources compared with 1 mile (urban) or >10 miles (rural) from a grocery store that provides a full range of meats, dairy products, grains, and vegetables (US Department of Agriculture, http://www.ers.usda.gov/data-products/food-access-research-atlas/go-to-the-atlas.aspx, last accessed April 3, 2017). Individuals living in food deserts often rely on convenience stores and fast-food chains that offer few, if any, healthy food choices, such as fruits and vegetables. The failure of supermarket chains to locate stores that offer fresh fruits and vegetables in inner-city communities—a form of food redlining—has had a profound effect on health. African American and Hispanic European American women are more likely to live in food deserts than non-Hispanic women of European or Asian descent.2Cummins S. Macintyre S. “Food deserts” - evidence and assumption in health policy making.BMJ. 2002; 325: 436-438Crossref PubMed Scopus (356) Google Scholar, 29Cummins S. Macintyre S. Food environments and obesity - neighbourhood or nation?.Int J Epidemiol. 2006; 35: 100-104Crossref PubMed Scopus (511) Google Scholar, 30Beaulac J. Kristjansson E. Cummins S. A Systematic review of food deserts, 1966-2007.Prev Chronic Dis. 2009; 6: A105PubMed Google Scholar Lack of healthy food choices puts African-American and Hispanic-American women at increased risk for insulin-resistance, type 2 diabetes (Figure 1), and obesity.2Cummins S. Macintyre S. “Food deserts” - evidence and assumption in health policy making.BMJ. 2002; 325: 436-438Crossref PubMed Scopus (356) Google Scholar, 29Cummins S. Macintyre S. Food environments and obesity - neighbourhood or nation?.Int J Epidemiol. 2006; 35: 100-104Crossref PubMed Scopus (511) Google Scholar, 30Beaulac J. Kristjansson E. Cummins S. A Systematic review of food deserts, 1966-2007.Prev Chronic Dis. 2009; 6: A105PubMed Google Scholar The lack of safe neighborhoods has a significant effect on obesity and metabolic health in African Americans. In a recent study, African Americans were 80% less likely to engage in physical activity than non-Hispanic European Americans (US Department of Health and Human Services, https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=4&lvlid=25, last accessed April 3, 2017). According to the 2013 Youth Risk Behavior Surveillance study, 21.5% of African American youth did not participate in at least 1 hour of daily physical activity during the prior week compared with 12.7% of non-Hispanic European American youth (CDC, https://www.cdc.gov/mmwr/preview/mmwrhtml/ss6304a1.htm, last accessed April 3, 2017). National studies have found that access to public parks, public pools, and green space is much lower in African American neighborhoods (National Recreation and Park Association, http://www.nrpa.org/uploadedFiles/nrpa.org/Publications_and_Research/Research/Papers/Parks-Rec-Underserved-Areas.pdf, last accessed April 3, 2017). Tellingly, African American children in neighborhoods that lack access to parks, playgrounds, and recreation centers have a 20% to 45% greater risk of becoming overweight (The State of Obesity, http://stateofobesity.org/disparities/blacks, last accessed April 3, 2017). Sidewalks in African American neighborhoods are 38 times more likely to be in poor condition, which is compounded by the threat of violence that strongly influences the amount of daily outdoor play that mothers permit their children.31Dias J.J. Whitaker R.C. Black mothers' perceptions about urban neighborhood safety and outdoor play for their preadolescent daughters.J Health Care Poor Underserved. 2013; 24: 206-219Crossref PubMed Scopus (26) Google Scholar Taken together, it is clear that disparities in exercise, access to parks and sidewalks, and a lack of safe neighborhoods disproportionately promote obesity and poor metabolic health in African Americans. BMI ≥30 kg/m2 is the most frequently used measure of obesity (CDC, https://www.cdc.gov/obesity/adult/defining.html, last accessed April 3, 2017).32Heymsfield S.B. Peterson C.M. Thomas D.M. Heo M. Schuna Jr., J.M. Why are there race/ethnic differences in adult body mass index-adiposity relationships? a quantitative critical review.Obes Rev. 2016; 17: 262-275Crossref PubMed Scopus (189) Google Scholar Although BMI is a commonly used measure, the appropriateness of BMI as a phenotypic marker of adiposity across populations differing in race and ethnicity is highly controversial,32Heymsfield S.B. Peterson C.M. Thomas D.M. Heo M. Schuna Jr., J.M. Why are there race/ethnic differences in adult body mass index-adiposity relationships? a quantitative critical review.Obes Rev. 2016; 17: 262-275Crossref PubMed Scopus (189) Google Scholar, 33Nelson D.A. Feingold M. Bolin F. Parfitt A.M. 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Abdominal obesity (WHR of ≥0.85 or waist circumference of ≥88 cm) is the second most frequently used measure of obesity (CDC, https://www.cdc.gov/obesity/adult/defining.html, last accessed April 3, 2017). WHR is thought to be a better measure than BMI of type 2 diabetes and metabolic risk in non-Hispanic European Americans (CDC, https://www.cdc.gov/obesity/adult/defining.html, last accessed April 3, 2017). However, the use of abdominal obesity in studies that include individuals of different races and ethnicities may be as problematic as the use of BMI because of the known racial and ethnic differences in body fat composition and distribution. For example, African American and non-Hispanic European American women have differences in muscle mass, fat distribution, bone mineral density, and bone mass.37Silva A.M. Shen W. Heo M. Gallagher D. Wang Z. Sardinha L.B. Heymsfield S.B. Ethnicity-related skeletal muscle differences across the lifespan.Am J Hum Biol. 2010; 22: 76-82Crossref PubMed Scopus (151) Google Scholar These differences lead to changes in visceral adipose tissue, which positively associates with hyperinsulinemia, insulin resistance, and metabolic syndrome (CDC, https://www.cdc.gov/obesity/adult/defining.html, last accessed April 3, 2017). In contrast, leg fat has the opposite correlation.41Hoyer D. Boyko E.J. McNeely M.J. Leonetti D.L. Kahn S.E. Fujimoto W.Y. Subcutaneous thigh fat area is unrelated to risk of type 2 diabetes in a prospective study of Japanese Americans.Diabetologia. 2011; 54: 2795-2800Crossref PubMed Scopus (17) Google Scholar Because African American women have an increased incidence of type 2 diabetes relative to non-Hispanic European American women,42Davis A.A. Kaklamani V.G. Metabolic syndrome and triple-negative breast cancer: a new paradigm.Int J Breast Cancer. 2012; 2012: 809291Crossref PubMed Google Scholar it would be anticipated that African American women would have a higher incidence of central obesity or increased visceral adipose tissue. However, the reverse is true. For a given BMI, waist circumference, or W
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