American Association for Cancer Research
10780432ccr111530-sup-f1_pdf_403k.pdf (403.77 kB)

Supplementary Figure 1 from Opposing Effects of Runx2 and Estradiol on Breast Cancer Cell Proliferation: In Vitro Identification of Reciprocally Regulated Gene Signature Related to Clinical Letrozole Responsiveness

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journal contribution
posted on 2023-03-31, 16:47 authored by Nyam-Osor Chimge, Sanjeev K. Baniwal, Jingqin Luo, Simon Coetzee, Omar Khalid, Benjamin P. Berman, Debu Tripathy, Matthew J. Ellis, Baruch Frenkel

PDF file - 403K, Cluster IV is linked to the mitotic polo-like kinase pathway. A, The 84 Cluster IV genes were analyzed for pathway enrichment using IPATM. Bars depict significance of enrichment represented by log p values. The line graph shows magnitudes of enrichment represented by ratios. B, Schematic illustration of the mitotic role of the polo-like kinase pathway (From IPATM), with green and red arrows representing responses to estradiol and Runx2, respectively, in the MCF7/Rx2dox cell culture model. Arrows are boxed to indicate Cluster IV genes, which by definition are stimulated by E2 and inhibited by Runx2.



Purpose: To assess the clinical significance of the interaction between estrogen and Runx2 signaling, previously shown in vitro.Experimental Design: MCF7/Rx2dox 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/Rx2dox 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/Rx2dox 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/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.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. Clin Cancer Res; 18(3); 901–11. ©2011 AACR.

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