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Evidences that estrogen receptor α interferes with adiponectin effects on breast cancer cell growth

Significance Statement

This study by Mauro et al demonstrate the mechanism of the cross-talk between adipoenctin and estrogen and its role in regulation of estrogen receptor alpha-positive breast cancer cells. The results of the study suggests this signaling pathway to be a potential target in breast cancer therapy.

Our study evidences that the globular form of adiponectin (gAdiponectin) binds to the specific receptor (Adipo R1), which in turn interacts, through the intracellular N terminus, with the adaptor protein APPL1. The activation of the AdipoR1-APPL1 induces the assembly of a multiprotein complex involving membrane ERα, IGF-IR and c-Src, all converging in MAPK activation. Moreover, it has been reported that membrane ERα, activating other membrane signaling, may in a long term contribute to a cascade of events triggering in MAPK activation, which in turn can transactivate ERα at nuclear level. Our results demonstrate that adiponectin is able to transactivate ERα in a ligand-independent manner, through the MAPK-induced phosphorylation of Serine118 located within AF-1 domain. In MCF-7 cells this leads to the classical features of ERα transactivation: nuclear localization, downregulation of mRNA and protein levels of ERα, and upregulation of estrogen-dependent genes. Thus, in breast cancer cells the activation of ERα promotes the transcription of genes involved in cell proliferation. Taken together, these data provide evidences that adiponectin, at the concentrations tested, induces transactivation of ERα and acts as a positive regulator of breast cancer growth.

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Figure: Effects of adiponectin on ERα-positive breast cancer cell growth The figure summarizes our proposed mechanism through which adiponectin, at relatively low concentrations, regulates growth in Estrogen Receptor alpha (ERα)-positive breast cancer cells.

 

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Mauro L, Pellegrino M, De Amicis F, Ricchio E, Giordano F, Rizza P, Catalano S, Bonofiglio D, Sisci D, Panno ML, Andò S.

Cell Cycle. 2014 Feb 15;13(4):553-64.

Department of Pharmacy, Health, and Nutritional Sciences; University of Calabria; Cosenza, Italy; Centro Sanitario; University of Calabria; Cosenza, Italy.

 

Abstract

 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 ERα+ MCF-7 cells while inhibiting proliferation of ERα- 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 ERα gene occurred. In addition, adiponectin induces rapid IGF-IR phosphorylation in MCF-7 cells, and the use of ERα} 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, ERα, 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 ERα in MCF-7 cells. We showed the classical features of ERα 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.

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