Leptin and Adiponectin Modulate the Self-renewal of Normal Human Breast Epithelial Stem Cells

Abstract

Multiple mechanisms are likely to account for the link between obesity and increased risk of post-menopausal breast cancer. Two adipokines, leptin and adiponectin, are of particular interest due to their opposing biological 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. By 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 to age-matched lean post-menopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared to only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the obesity-driven increase in post-menopausal 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.

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Serum from obese patients increased a breast cancer stem cell population by 30% compared with 7% for lean control serum [103]. In breast cancer cell lines, silencing the leptin receptor may reduce cancer stem cell-like properties and EMT transition [104], and treatment of breast cancer cells with leptin from tumour stroma induced stem-like properties [105].…”

Obesity and cancer: inflammation bridges the two

“…Leptin is known to be pro-tumorigenic and to act directly on breast epithelial cells to promote proliferation, by promoting estrogen signaling, activation of MAPKs and STAT3 signaling, and inhibition of apoptosis by activation of AKT signaling [46]. Leptin is also pro-angiogenic and has been shown to promote epithelial-mesenchymal transition (EMT) in breast cancer and to promote the self-renewal of mammary stem cells and breast cancer stem cells [47–49]. Adiponectin has been shown to be anti-tumorigenic in the breast, as systemically low level of adiponectin is associated with increased lymph node metastasis and more aggressive tumors [50].…”

Stromal-Epithelial Interactions during Mammary Gland Development

“…Leptin and adiponectin are the most extensively studied hormones synthesized by adipose tissue. They are found in higher concentrations in the mammary tissue than in blood and thus may be a part of an important paracrine or juxtacrine signaling system between adipose-rich stroma and epithelial cells [24]. Leptin, which was the first known adipokine discovered by Friedman and Coleman in 1994, is a 16 kDa nonglycosylated protein encoded by the Ob gene.…”

“…In contrast, unopposed adiponectin decreases the size of the mammary stem cell pool in vitro. It is believed that leptin and adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool [24].…”