Evidences that Estrogen Receptor alpha interferes with adiponectin effects on breast cancer cell growth

Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, anti-inflammatory, antiatherogenic, and antiproliferative properties. In addition, it appears to play an important role also in the development and progression of several obesity-related malignancies, including breast cancer. Here, we demonstrated that adiponectin induces a dichotomic effect on breast cancer growth. Indeed, it stimulates growth in ER alpha+ MCF-7 cells while inhibiting proliferation of ER alpha- MDA-MB-231 cells. Notably, only in MCF-7 cells adiponectin exposure exerts a rapid activation of MAPK phosphorylation, which is markedly reduced when knockdown of the ER alpha gene occurred. In addition, adiponectin induces rapid IGF-IR phosphorylation in MCF-7 cells, and the use of ER alpha siRNA prevents this effect. Moreover, MAPK activation induced by adiponectin was reversed by IGF-IR siRNA. Coimmunoprecipitation studies show the existence of a multiprotein complex involving AdipoR1, APPL1, ER alpha, IGF-IR, and c-Src that is responsible for MAPK signaling activation in ER alpha+ positive breast cancer cells. It is well known that in addition to the rapid effects through non-genomic mechanisms, ER alpha also mediates nuclear genomic actions. In this concern, we demonstrated that adiponectin is able to transactivate ER alpha in MCF-7 cells. We showed the classical features of ER alpha transactivation: nuclear localization, downregulation of mRNA and protein levels, and upregulation of estrogen-dependent genes. Thus, our study clarifies the molecular mechanism through which adiponectin modulates breast cancer cell growth, providing evidences on the cell-type dependency of adiponectin action in relationship to ER alpha status.