Abstract 1471: HER2 regulated miRNA expression in letrozole resistant breast cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA MicroRNAs (miRNAs) are short non-coding regulatory RNA molecules that modulate the expression of specific proteins by binding to target messenger RNAs (mRNAs) and causing either degradation of the mRNAs or inhibition of their translation to protein. Thus, miRNAs play an important role in a variety of normal cellular processes (e.g., differentiation, cell growth, cell death, etc.), and in diseases, such as cancer. MiRNAs have been implicated in breast cancer, but very little is known about their role in aromatase-inhibitor (AI)-resistant breast cancer. Studies by us and others suggest that acquired resistance to AIs (e.g., letrozole, let), which inhibit the aromatase enzyme from converting androgens (e.g., androstenedione) to estrogen, involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as epidermal growth factor receptor (EGFR)/HER2. Recent work in our lab has further indicated that HER2's effects on resistance are mediated by hypoxia inducible factor 1 (HIF-1) and cancer stem cells. The aim of this current study was to determine if miRNAs were also involved in this mechanism. Initial miRNA microarray results by Zhou et al. identified a number of miRNAs that were either upregulated or down regulated in ER-/HER2+, let-resistant LTLTCa cells vs. ER+/HER2- let-sensitive MCF-7Ca cells. Of particular interest, was data indicating increased expression of miRNA181a and miRNA222 in LTLTCa cells. MiRNA181a has been linked to HIF-1 and cancer stem cells. MiRNA222 has been linked to drug resistance in breast cancer cells. In vitro miRNA isolation and RT-PCR analyses confirmed the microarray results: miRNA181a and miRNA22 levels were at least 13-fold and 10-fold higher in LTLTCa cells vs. MCF-7Ca cells, respectively. MiRNA expression was also analyzed in mouse tumor xenografts. Compared to control (androstenedione-supplemented) tumors, let-treated tumors had increased miRNA181a and 222 expression, starting at 2 weeks of let treatment, when HER2 has previously been shown to be expressed, and further increasing through 16 weeks of letrozole treatment, when tumors are letrozole-resistant. Since HER2 is associated with let resistance, the effect of inhibiting HER2 expression and/or activity on miRNA expression was determined. Lapatinib and trastuzumab either alone or in combination, significantly decreased miRNA 181a expression (0.1-fold vs. vehicle). MiRNA 181a and 222 expression was also analyzed in another ER-/HER2+ breast cancer cell line, SKBR3. Compared to MCF-7Ca cells, miRNA 181a, but not miRNA 222, was significantly upregulated 16-fold in SKBR3 cells. Lastly, preliminary studies were conducted to look at miRNA181a expression in patient tumor samples. Significant and comparable levels of miRNA181a were detected in both ER+/HER2+, ER-/HER2+ samples Overall, these results suggest that miRNAs 181a and 222 are regulated by HER2 and may mediate its effects on AI-resistance. Note: This abstract was not presented at the meeting. Citation Format: Armina A. Kazi, Gauri Sabnis, Qun Zhou, Saranya Chumsri, Amanda Schech, Preeti Shah, Angela Brodie. HER2 regulated miRNA expression in letrozole resistant breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1471. doi:10.1158/1538-7445.AM2014-1471