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CARM1 is an important determinant of ER?-dependent breast cancer cell differentiation and proliferation in breast cancer cells.

ABSTRACT: Breast cancers with estrogen receptor ? (ER?) expression are often more differentiated histologically than ER?-negative tumors, but the reasons for this difference are poorly understood. One possible explanation is that transcriptional cofactors associated with ER? determine the expression of genes which promote a more differentiated phenotype. In this study, we identify one such cofactor as coactivator-associated arginine methyltransferase 1 (CARM1), a unique coactivator of ER? that can simultaneously block cell proliferation and induce differentiation through global regulation of ER?-regulated genes. CARM1 was evidenced as an ER? coactivator in cell-based assays, gene expression microarrays, and mouse xenograft models. In human breast tumors, CARM1 expression positively correlated with ER? levels in ER-positive tumors but was inversely correlated with tumor grade. Our findings suggest that coexpression of CARM1 and ER? may provide a better biomarker of well-differentiated breast cancer. Furthermore, our findings define an important functional role of this histone arginine methyltransferase in reprogramming ER?-regulated cellular processes, implicating CARM1 as a putative epigenetic target in ER-positive breast cancers.

SUBMITTER: Al-Dhaheri M

PROVIDER: S-EPMC3076802 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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CARM1 is an important determinant of ERα-dependent breast cancer cell differentiation and proliferation in breast cancer cells.

Al-Dhaheri Mariam M Wu Jiacai J Skliris Georgios P GP Li Jun J Higashimato Ken K Wang Yidan Y White Kevin P KP Lambert Paul P Zhu Yuerong Y Murphy Leigh L Xu Wei W

Cancer research 20110131 6

Breast cancers with estrogen receptor α (ERα) expression are often more differentiated histologically than ERα-negative tumors, but the reasons for this difference are poorly understood. One possible explanation is that transcriptional cofactors associated with ERα determine the expression of genes which promote a more differentiated phenotype. In this study, we identify one such cofactor as coactivator-associated arginine methyltransferase 1 (CARM1), a unique coactivator of ERα that can simulta ...[more]

PMID: 21282336

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Project description:Background: Some stemness-associated transcription factors consistently play essential roles in the maintenance of pluripotency or induce the differentiation of cancer stem cells (CSCs). However, the regulatory mechanism of CSC stemness mediated by transcription factors has not been extensively explored. Here, we show that two transcription factors (YB-1 and ER?), which are simultaneously highly expressed in estrogen receptor (ER)-positive CSCs, interact with each other to regulate the stemness and differentiation of ER-positive CSCs. Methods: The expression of YB-1 was examined in ER-positive CSCs and patient specimens. Western blot, real-time PCR, cell viability analysis, tumorsphere formation assay and subcutaneous tumorigenesis assays were used to study the stemness functions of YB-1 and ER? in CSCs. The relationship between YB-1 and ER? in cells was studied by promoter activity analysis, the electrophoretic mobility shift assay (EMSA) and the Co-IP assay. The mechanisms and functional significance of YB-1 in the sensitivity of CSCs to tamoxifen were further investigated with both in vitro and in vivo models. Results: YB-1 was aberrantly upregulated in the cancerous tissue of ER-positive breast cancer patients and in CSCs. Knockdown of YB-1 in ER-positive CSCs significantly inhibited cell stemness and induced differentiation, and the expression of YB-1 could be regulated by estrogen signaling and ER? in ER-positive breast CSCs. The Co-IP results showed that YB-1 interacted directly with ER? specifically in ER-positive non-CSCs and that YB-1 induced ER? degradation by ubiquitination via direct interaction in differentiated cells. Cell differentiation induced by FBS could inhibit YB-1 phosphorylation and promote YB-1 protein transfer from the nucleus to the cytoplasm. Moreover, cell differentiation induced by targeting inhibited the expression of YB-1 in ER-positive CSCs, which increased the sensitivity of cells to tamoxifen in vitro and in vivo. Conclusion: The ER?/YB-1 axis has an important role in the regulation of ER-positive breast cancer stemness. The dephosphorylation of YB-1 and the interaction between YB-1 and ER? may be the switch that initiates the differentiation of ER-positive CSCs. Targeting YB-1 to sensitize ER-positive CSCs to antiestrogen therapy might represent a new therapeutic strategy that warrants further exploration.

Dataset Information

CARM1 is an important determinant of ER?-dependent breast cancer cell differentiation and proliferation in breast cancer cells.

Publications

CARM1 is an important determinant of ERα-dependent breast cancer cell differentiation and proliferation in breast cancer cells.

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