TY - JOUR
T1 - Opposing effects of Runx2 and estradiol on breast cancer cell proliferation
T2 - In vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness
AU - Chimge, Nyam Osor
AU - Baniwal, Sanjeev K.
AU - Luo, Jingqin
AU - Coetzee, Simon
AU - Khalid, Omar
AU - Berman, Benjamin P.
AU - Tripathy, Debu
AU - Ellis, Matthew J.
AU - Frenkel, Baruch
PY - 2012/2/1
Y1 - 2012/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84856523566&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-1530
DO - 10.1158/1078-0432.CCR-11-1530
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C2 - 22147940
AN - SCOPUS:84856523566
SN - 1078-0432
VL - 18
SP - 901
EP - 911
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -
