To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously demonstrated in vitro.

MCF7/Rx2dox BCa 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/Rx2dox system was analyzed in pre- and on-treatment biopsies from hormone receptor-positive patients undergoing neo-adjuvant 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/Rx2dox cells treated with estradiol and/or doxycycline demonstrated reciprocal attenuation of Runx2 and estrogen signaling. Correspondingly in BCa tumors, expression of estradiol- and Runx2-regulated genes was inversely correlated; and, letrozole increased expression of Runx2-stimulated genes as defined in the MCF7/Rx2dox 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 BCa. 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.

PMID: 22147940 [PubMed - as supplied by publisher] Source: National Library of Medicine.