Abstract 310: Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen coordinating a crosstalk between Med1, miR205 and Erb B kinases
Authors: Nagalingam Arumugam , Muniraj Nethaji , Siddharth Sumit , Avtanski Dimiter. B , Parida Sheetal , Kuppusamy Panjamurthy , Győrffy Balázs , Saxena Neeraj , Sharma Dipali 
Published: August 2019

Background and Aim: Obese state is associated with increased breast cancer growth, metastatic progression, poor overall survival and poor response to therapy. Analyses of clinical trial population showed that obesity associates with poor outcomes in patients with estrogen receptor (ER)-positive breast cancer treated with standard chemohormonal therapy. A characteristic feature of obesity is hyperleptinemia (high leptin levels) which mediates the biological effects of obesity. In this study, we seek to decipher the underlying molecular mechanisms by which obesity/hyperleptinemia reduces the efficacy of tamoxifen.

Results: Obese mice models exhibiting hyperleptinemia supported larger tumors and responded poorly to tamoxifen therapy. Kaplan meier analyses showed that high leptin and high leptin receptor levels associates with poor prognosis in ER positive breast cancer. Indeed, leptin treatment abrogated tamoxifen-mediated inhibition of clonogenicity, and soft-agar colony formation. Leptin treatment increased breast tumor growth and significantly reduced the efficacy of tamoxifen. At the molecular level, leptin induced nuclear translocation of pER (ser 118 and ser 167) and increased the expression of ER-responsive genes while reducing tamoxifen-mediated gene repression. Tamoxifen is known to recruit corepressors to ER-responsive genes. ChIP analysis revealed that tamoxifen-induced recruitment of NCoR, SMRT and Mi2 corepressors was abrogated in the presence of leptin. We found that Med1, anchor subunit of human mediator complex, interacts with various key effector molecules of leptin-signaling network and potentially associates with 48 (out of 75) obesity-signature genes indicating its functional importance. Further, we found that leptin upregulated Med1 via decreasing miR-205 and increased its functional activation via phosphorylation, nuclear translocation and promoter-recruitment. Med1 phosphorylation was mediated by activation of Her2 and EGFR in response to leptin. It is important to note that silencing of Med1 abrogated the negative effects of leptin on tamoxifen efficacy. Bioactive strategies using honokiol or adiponectin treatment effectively inhibited leptin-induced Med1 expression and increased the efficacy of tamoxifen even in the presence of leptin.

Conclusion: In conclusion, these studies show the molecular mechanisms by which obese state may contribute to poor response to endocrine therapy. We show that activation of Med1 via leptin-induced EGFR and Her2 kinases act as the key node mediating the negative effects of leptin on tamoxifen efficacy. A combination regimen of honokiol and adiponectin with tamoxifen may increase its efficacy in obese state.

Citation Format: Arumugam Nagalingam, Nethaji Muniraj, Sumit Siddharth, Dimiter. B Avtanski, Sheetal Parida, Panjamurthy Kuppusamy, Balázs Győrffy, Neeraj Saxena, Dipali Sharma. Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen coordinating a crosstalk between Med1, miR205 and Erb B kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 310.