Multiple mechanisms are likely to account for the link between
obesity and increased risk of postmenopausal
breast cancer. Two
adipokines,
leptin and
adiponectin, are of particular interest due to their opposing biologic functions and associations with
breast cancer risk. In the current study, we investigated the effects of
leptin and
adiponectin on normal breast epithelial stem cells. Levels of
leptin in human adipose explant-derived
conditioned media positively correlated with the size of the normal breast stem cell pool. In contrast, an inverse relationship was found for
adiponectin. Moreover, a strong linear relationship was observed between the
leptin/
adiponectin ratio in adipose
conditioned media and breast stem cell self-renewal. Consistent with these findings, exogenous
leptin stimulated whereas
adiponectin suppressed breast stem cell self-renewal. In addition to local in-breast effects, circulating factors, including
leptin and
adiponectin, may contribute to the link between
obesity and
breast cancer. Increased levels of
leptin and reduced amounts of
adiponectin were found in serum from obese compared with age-matched lean postmenopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared with only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the
obesity-driven increase in postmenopausal
breast cancer risk.
Leptin and
adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool. Interventions that disrupt this axis and thereby normalize breast stem cell self-renewal could reduce the risk of
breast cancer.