Abstract
Obesity is associated with an increased risk of breast cancer in post-menopausal women and decreased risk in pre-menopausal women. Conversely, in BRCA1/2 mutation carriers, pre-menopausal obesity is associated with early-onset breast cancer. Here we show that obese, pre-menopausal BRCA1/2 mutation carriers have increased levels of aromatase and inflammation in the breast, as occurs in post-menopausal women. In a prospective cohort study of 141 women with germline BRCA1 (n = 74) or BRCA2 (n = 67) mutations, leptin, and aromatase expression were higher in the breast tissue of obese versus lean individuals (P < 0.05). Obesity was associated with breast white adipose tissue inflammation, which correlated with breast aromatase levels (P < 0.01). Circulating C-reactive protein, interleukin-6, and leptin positively correlated with body mass index and breast aromatase levels, whereas negative correlations were observed for adiponectin and sex hormone-binding globulin (P < 0.05). These findings could help explain the increased risk of early-onset breast cancer in obese BRCA1/2 mutation carriers.
Highlights
Mutant BRCA1 and BRCA2 DNA repair enzymes are causally linked to an increased risk of several malignancies including breast and ovarian cancers[1]
Previous studies that did not focus on BRCA1/2 mutation carriers demonstrated that levels of aromatase in the breast positively correlate with body mass index (BMI), breast adipocyte size, and white adipose tissue inflammation (WATi) manifested as crown-like structures of the breast (CLS-B)[15,16]
We investigated the relationship between BMI, leptin, and aromatase expression in the breast tissue of both BRCA1 and BRCA2 mutation carriers
Summary
Mutant BRCA1 and BRCA2 DNA repair enzymes are causally linked to an increased risk of several malignancies including breast and ovarian cancers[1]. Previous epidemiological studies have suggested that obesity prior to menopause is associated with elevated risk and earlier onset of breast cancer in BRCA mutation carriers[2,3]. In unselected, predominantly wild-type populations, obesity is associated with a decreased risk of pre-menopausal breast cancer[4,5,6,7,8]. Post-menopausal status is independently associated with breast WATi, which contributes to elevated breast cancer risk in this population[16]. Pre- or post-menopausal women with impairments in DNA repair due to germline BRCA1/2 mutations may be more suceptible to the pro-mutagenic and pro-proliferative effects of free estrogens, which could lead to increased breast cancer risk
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