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Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness.


ABSTRACT: To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously shown in vitro.MCF7/Rx2(dox) breast cancer cells were treated with estradiol and/or doxycycline to induce Runx2, and global gene expression was profiled to define genes regulated by estradiol, Runx2, or both. Anchorage-independent growth was assessed by soft-agar colony formation assays. Expression of gene sets defined using the MCF7/Rx2(dox) system was analyzed in pre- and on-treatment biopsies from hormone receptor-positive patients undergoing neoadjuvant letrozole treatment in two independent studies, and short-term changes in gene expression were correlated with tumor size reduction or Ki67 index at surgery.Reflecting its oncogenic property, estradiol strongly promoted soft-agar colony formation, whereas Runx2 blocked this process suggesting tumor suppressor property. Transcriptome analysis of MCF7/Rx2(dox) cells treated with estradiol and/or doxycycline showed reciprocal attenuation of Runx2 and estrogen signaling. Correspondingly in breast cancer tumors, expression of estradiol- and Runx2-regulated genes was inversely correlated, and letrozole increased expression of Runx2-stimulated genes, as defined in the MCF7/Rx2(dox) model. Of particular interest was a gene set upregulated by estradiol and downregulated by Runx2 in vitro; its short-term response to letrozole treatment associated with tumor size reduction and Ki67 index at surgery better than other estradiol-regulated gene sets.This work provides clinical evidence for the importance of antagonism between Runx2 and E2 signaling in breast cancer. Likely sensing the tension between them, letrozole responsiveness of a genomic node, positively regulated by estradiol and negatively regulated by Runx2 in vitro, best correlated with the clinical efficacy of letrozole treatment.

SUBMITTER: Chimge NO 

PROVIDER: S-EPMC3277803 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness.

Chimge Nyam-Osor NO   Baniwal Sanjeev K SK   Luo Jingqin J   Coetzee Simon S   Khalid Omar O   Berman Benjamin P BP   Tripathy Debu D   Ellis Matthew J MJ   Frenkel Baruch B  

Clinical cancer research : an official journal of the American Association for Cancer Research 20111206 3


<h4>Purpose</h4>To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously shown in vitro.<h4>Experimental design</h4>MCF7/Rx2(dox) breast cancer cells were treated with estradiol and/or doxycycline to induce Runx2, and global gene expression was profiled to define genes regulated by estradiol, Runx2, or both. Anchorage-independent growth was assessed by soft-agar colony formation assays. Expression of gene sets defined using the MCF7/Rx2(dox) system  ...[more]

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