Abstract
Breast cancer develops over a timeframe of 2–3 decades prior to clinical detection. Given this prolonged latency, it is somewhat unexpected from a biological perspective that obesity has no effect or reduces the risk for breast cancer in premenopausal women yet increases the risk for breast cancer in postmenopausal women. This conundrum is particularly striking in light of the generally negative effects of obesity on breast cancer outcomes, including larger tumor size at diagnosis and poorer prognosis in both pre- and postmenopausal women. This review and analysis identifies factors that may contribute to this apparent conundrum, issues that merit further investigation, and characteristics of preclinical models for breast cancer and obesity that should be considered if animal models are used to deconstruct the conundrum.
Highlights
Breast cancer develops over a timeframe of 2–3 decades prior to clinical detection
The predominant hypothesis invoked to explain the increased risk conferred by obesity centers on peripheral production of sex hormones by fat tissue; the higher rates of conversion of androgenic precursors to estradiol through increased aromatase enzyme activity, a process known as aromatization [14]
In women with primary breast cancer diagnosis recruited to the Health, Eating, Activity, and Lifestyle (HEAL) Study, circulating levels of inflammatory biomarkers serum amyloid A (SAA) and C-reactive protein were associated with reduced disease-free survival (comparison of highest to lowest tertiles, SAA: hazard ratio (HR) = 2.91; CRP: HR = 2.05) [79]
Summary
In 2012, 1.7 million new cases of breast cancer were diagnosed globally, and breast cancer was responsible for nearly 700,000 deaths. Relative to factors unrelated to lifestyle, seven breast cancer susceptibility genes or gene sets with high penetrance (relative risk > 5) have been identified in which germline mutations are associated with increased breast cancer risk in an inherited Mendelian fashion [3]. These genes are: DNA damage repair genes BRCA1/2, cell–cell adhesion gene CDH1, tumor suppressor phosphatase and tensin homolog PTEN, serine threonine kinase SKT11, tumor suppressor TP53, and DNA mismatch repair genes MLH1, MSH2/6, and PMS2 [3]. These seven genes are cumulatively found to be drivers in only 5%–10% of all breast cancer cases, leaving the majority of breast cancer cases attributable to a complex summation of genetic and epigenetic alterations on which personal choices, generally categorized as environmental exposures, are thought to operate
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