Med1 plays a critical role in the development of tamoxifen resistance

Abstract

Understanding the molecular pathways that contribute to the development of tamoxifen resistance is a critical research priority as acquired tamoxifen resistance is the principal cause of poor prognosis and death of patients with originally good prognosis hormone-responsive breast tumors. In this report, we provide evidence that Med1, an important subunit of mediator coactivator complex, is spontaneously upregulated during acquired tamoxifen-resistance development potentiating agonist activities of tamoxifen. Phosphorylated Med1 and estrogen receptor (ER) are abundant in tamoxifen-resistant breast cancer cells due to persistent activation of extracellular signal-regulated kinases. Mechanistically, phosphorylated Med1 exhibits nuclear accumulation, increased interaction with ER and higher tamoxifen-induced recruitment to ER-responsive promoters, which is abrogated by inhibition of Med1 phosphorylation. Stable knockdown of Med1 in tamoxifen-resistant cells not only reverses tamoxifen resistance in vitro but also in vivo. Finally, higher expression levels of Med1 in the tumor significantly correlated with tamoxifen resistance in ER-positive breast cancer patients on adjuvant tamoxifen monotherapy. In silico analysis of breast cancer, utilizing published profiling studies showed that Med1 is overexpressed in aggressive subsets. These findings provide what we believe is the first evidence for a critical role for Med1 in tamoxifen resistance and identify this coactivator protein as an essential effector of the tamoxifen-induced breast cancer growth.

Mechanistic Elucidation of the Antitumor Properties of Withaferin A in Breast Cancer

“…Cellular cytosolic and nuclear fractions were prepared following previously published protocol (25). Immunoblotting was carried out as described (26).…”

Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis

“…Phosphorylation of Med1 by ERK and/or AKT in prostate cancer cells augments androgen receptor transcriptional activity, which in turn enhances Med1 overexpression and upregulation of genes involved in inflammation, cell cycle progression, and survival (102). Persistent activation of ERK/MAPK leads to Med1 overexpression, resulting in ER-positive breast cancer cells resistant to tamoxifen (112). Phosphorylated Med1 exhibits nuclear accumulation, increased recruitment of ER–Med1 complex on the promoter of ER-responsive upon tamoxifen treatment (112).…”

“…Persistent activation of ERK/MAPK leads to Med1 overexpression, resulting in ER-positive breast cancer cells resistant to tamoxifen (112). Phosphorylated Med1 exhibits nuclear accumulation, increased recruitment of ER–Med1 complex on the promoter of ER-responsive upon tamoxifen treatment (112). Recently, phosphorylation of Med1 by energy-sensing kinase AMP-activated protein kinase (AMPK) was demonstrated (20).…”

Endocrine resistance in breast cancer: From cellular signaling pathways to epigenetic mechanisms

“…MED1, a subunit of mediator coactivator complex acting as a link between transcription factors and RNA polymerase II, was shown to be upregulated and phosphorylated by persistent ERK pathway activation during acquired TAM-resistance development. 20 Overexpression of MED1 is associated with aggressiveness and decrease of AE-response failure. Mutation of ERα and expression of a truncated variant named ERα36 have also been reported in references 8 and 9.…”