Abstract LB-57: Integral role of Med1 in conferring tamoxifen resistance to poor prognosis (luminal-B) estrogen receptor positive breast cancer
Authors: Nagalingam Arumugam , Oprea-Ilies Gabriela M. , Taliaferro-Smith LaTonia , Cohen Cynthia , Saxena Neeraj K. , Sharma Dipali 
Published: February 2011

Background: Gene expression studies have identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Some luminal B tumors can be identified by their expression of Her2 but the major biological distinction between luminal A and luminal B is their proliferation signature. Upon treatment with adjuvant tamoxifen, luminal A breast tumors show a good prognosis, however the clinical outcome of luminal B breast tumor is poor. The underlying mechanisms for the differential response to adjuvant tamoxifen therapy between luminal A and luminal B breast tumors are probably multifactorial and remain largely unknown. In this study, we examined the molecular mechanisms contributing to the poor prognosis of the luminal B ER-positive breast cancer subtype in response to tamoxifen.

Methods and Results: We developed a physiologically relevant luminal B ER-positive breast cancer (luminal B) model. This cell line model exhibited an elevated growth factor signaling pathway. We showed that tamoxifen treatment inhibited clonogenicity and anchorage-independent growth of luminal A breast cancer cells. Interestingly, acting as a potent agonist, tamoxifen resulted in significantly increased clonogenicity and anchorage-independent growth in luminal B cells. We found that tamoxifen also increased expression of ER-responsive genes in luminal B cells in contrast to luminal A cells where it effectively inhibited ER-transactivation and ER-responsive gene expression. Mediator complex is an essential coactivator complex for the expression of ER-responsive genes. Investigating the underlying mechanisms, we discovered that anchor subunit of mediator coactivator complex, Med1, was overexpressed in luminal B cells. Furthermore, we found hyper-phosphorylation of Med1 and ER in luminal B cells due to persistent activation of ERK. Hyper-phosphorylated Med1 showed increased recruitment to ER-responsive promoters in the presence of tamoxifen in luminal B cells. Stably silencing Med1 in luminal B cells not only inhibited tamoxifen-induced clonogenicity and anchorage-independent growth, it also inhibited tamoxifen-induced ER-transactivation. These data clearly showed the essential role of Med1 in mediating tamoxifen response in luminal B cells.

Conclusions: These data demonstrate a novel role of Med1 in promotion of tamoxifen-induced growth of luminal B breast cancer cells and suggest that inhibiting Med1/or its activation may prove to be beneficial to overcome/reduce poor prognosis of basal B breast tumors. This conclusion is supported by in vivo data showing overexpression of Med1 in luminal B estrogen receptor-positive breast tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-57.