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

Nyam Osor Chimge, Sanjeev K. Baniwal, Jingqin Luo, Simon Coetzee, Omar Khalid, Benjamin P. Berman, Debu Tripathy, Matthew J. Ellis, Baruch Frenkel

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Purpose: To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously shown in vitro. Experimental Design: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)901-911
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2012

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