Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2.

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1+/- mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.

Three-dimensional growth of breast cancer cells potentiates the anti-tumor effects of unacylated ghrelin and AZP-531.

Breast cancer is the most common type of cancer in women and notwithstanding important therapeutic advances, remains the second leading cause of cancer-related death. Despite extensive research relating to the hormone ghrelin, responsible for the stimulation of growth hormone release and appetite, little is known of the effects of its unacylated form, especially in cancer. The present study aimed to characterize effects of unacylated ghrelin on breast cancer cells, define its mechanism of action, and explore the therapeutic potential of unacylated ghrelin or analog AZP-531. We report potent anti-tumor effects of unacylated ghrelin, dependent on cells being cultured in 3D in a biologically-relevant extracellular matrix. The mechanism of unacylated ghrelin-mediated growth inhibition involves activation of Gαi and suppression of MAPK signaling. AZP-531 also suppresses the growth of breast cancer cells in vitro and in xenografts, and may be a novel approach for the safe and effective treatment of breast cancer.

Estrogens and breast cancer: Mechanisms involved in obesity-related development, growth and progression.

Obesity is a risk factor for estrogen receptor-positive (ER+) breast cancer after menopause. The pro-proliferative effects of estrogens are well characterized and there is a growing body of evidence to also suggest an important role in tumorigenesis. Importantly, obesity not only increases the risk of breast cancer, but it also increases the risk of recurrence and cancer-associated death. Aromatase is the rate-limiting enzyme in estrogen biosynthesis and its expression in breast adipose stromal cells is hypothesized to drive the growth of breast tumors and confer resistance to endocrine therapy in obese postmenopausal women. The molecular regulation of aromatase has been characterized in response to many obesity-related molecules, including inflammatory mediators and adipokines. This review is aimed at providing an overview of our current knowledge in relation to the regulation of estrogens in adipose tissue and their role in driving breast tumor development, growth and progression.