TY - JOUR
T1 - Leptin and adiponectin modulate the self-renewal of normal human breast epithelial stem cells
AU - Esper, Raymond M.
AU - Dame, Michael
AU - Mcclintock, Shannon
AU - Holt, Peter R.
AU - Dannenberg, Andrew J.
AU - S.wicha, Max
AU - Brenner, Dean E.
N1 - Funding Information:
This work was supported by The Kutsche Memorial Chair in Internal Medicine (to D.E. Brenner); The Cancer Center Thomas Fund for Cancer Prevention (to D.E. Brenner); NCI T32 Training Grant: 5 T32 CA 9357-32 (to Kathleen Cooney); grant #UL1 TR000043 from the National Center for Advancing Translational Sciences [NCATS, NIH Clinical and Translational Science (CTSA) program and cosponsored by the Center for Basic and Translational Research on Disorders of the Digestive System at Rockefeller University]; grant NIH/NCI R01CA154481, the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick), the Breast Cancer Research Foundation (to A.J. Dannenberg), and the Sackler Center for Biomedicine and Nutrition Research (to P.R. Holt).
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/12
Y1 - 2015/12
N2 - 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 agematched 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 selfrenewal could reduce the risk of breast cancer.
AB - 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 agematched 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 selfrenewal could reduce the risk of breast cancer.
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U2 - 10.1158/1940-6207.CAPR-14-0334
DO - 10.1158/1940-6207.CAPR-14-0334
M3 - Article
C2 - 26487401
AN - SCOPUS:84951922542
VL - 8
SP - 1174
EP - 1183
JO - Cancer Prevention Research
JF - Cancer Prevention Research
SN - 1940-6207
IS - 12
ER -