Paracrine effects of adipocytes on mammary epithelial cell cycle regulation

Abstract

To establish a molecular link between obesity and cancer we examined the paracrine role of adipocytes on MCF7 cell cycle regulation. Arrested MCF7 cells were treated with leptin (LEP) and adiponectin (ADIPO). p27 protein levels decreased and increased with LEP and ADIPO, respectively, suggesting adipokine‐mediated MCF7 cell cycle regulation. Addition of LEP overcame the effects of ADIPO on p27 protein levels. Selective JAK2 inhibition had no effect on LEP‐dependent cell cycle entry. Inhibition of AKT enhanced the ADIPO effects on p27 protein and prevented LEP‐dependent amelioration of ADIPO effects on p27 protein. Co‐culture of MCF7 cells with adipocytes from lean rats, which secreted low levels of LEP and high levels of ADIPO, increased p27 and decreased cyclin E protein while inducing cell cycle withdrawal, as measured by FACS analyses, in MCF7 cells. Co‐culture with adipocytes from obese rats, which secreted high LEP and low ADIPO, reduced p27 and cyclin E protein levels and induced MCF7 cell cycle entry. Addition of exogenous ADIPO to obese adipocyte co‐cultures inhibited the effects of these adipocytes on MCF7 cell cycle regulation, indicated by an increase in p27 and decrease in cyclin E protein and MCF7 cell cycle withdrawal. Our data suggest that ADIPO and LEP exert opposite effects on mammary cell cycle regulation and that altering the ratio of these adipokines has dramatic effects on MCF7 cell cycle status.