Abstract
Alterations in estrogen-mediated cellular signaling have largely been implicated in the pathogenesis of breast cancer. Here, we investigated the signaling regulation of a splice variant of the estrogen receptor, namely estrogen receptor (ERα-36), associated with a poor prognosis in breast cancers. Coupling in vitro and in vivo approaches we determined the precise sequential molecular events of a new estrogen signaling network in an ERα-negative cell line and in an original patient-derived xenograft. After estrogen treatment, ERα-36 rapidly associates with Src at the level of the plasma membrane, initiating downstream cascades, including MEK1/ERK activation and paxillin phosphorylation on S126, which in turn triggers a higher expression of cyclin D1. Of note, the direct binding of ERα-36 to ERK2 prevents its dephosphorylation by MKP3 and enhances the downstream signaling. These findings improve our understanding of the regulation of non-genomic estrogen signaling and open new avenues for personalized therapeutic approaches targeting Src or MEK in ERα-36-positive patients.
Highlights
Estrogen signaling is essential in the initiation and development of human breast cancers
The wild-type (WT) ERα-36 was localized in the cytoplasm and at the level of the plasma membrane (Figure 1Bd-f), whereas the mutants were mainly detected in the nucleus (Figure 1B(g–l))
We evaluated the level of expression of ERα-36 in a panel of human breast cancer cell lines, as well as in patient-derived xenograft (PDX) models.[23]
Summary
Estrogen signaling is essential in the initiation and development of human breast cancers. The biological actions of estrogen are mediated through estrogen receptor ERα and ERβ, which function in the nucleus in a ligand-dependent manner, composed of functional domains,[1] including (i) the variable N-terminal A/B domain containing the transactivation domain AF-1, (ii) the C or DNA-binding domain, (iii) the hinge domain (D) and (iv) the E/F domains containing the ligand-binding domain (LBD) and the transactivation domain AF-2.2 Several ERα variants, derived from the alternative mRNA splicing of ESR1 gene, have been reported,[3] including ERα-36.4 The transcription of ERα-36 is initiated by a previously unidentified promoter located in the first intron of the ESR1 gene. The ERα-36 signaling pathway contributes to the potential invasion and metastasis of cancer cells,[13] and interestingly, ERα-36 is expressed in ERα-negative breast cancer cell lines and ERα-negative tumor samples.[14,15,16,17] Intriguingly, ERα-36 can stimulate ERK activation in cells treated with the anti-estrogen tamoxifen,[17,18] and is involved in the development of tamoxifen resistance in ERα-positive breast cancer cell lines.[19,20] In ERα-negative breast cancer cell lines, ERα-36 induces paclitaxel resistance through c-jun N-terminal kinases, a component of the ERK family.[21]
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