Abstract LB-212: Ionizing radiation selectively promotes invasion of ErbB2-expressing breast cancer cells via regulation of FoxM1

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL ErbB2 is frequently amplified in premalignant breast cancers including ductal carcinoma in situ (DCIS); however, little is known about the signals or pathways it modulates in the progression into the invasive/malignant state. Radiotherapy is often used to treat early premalignant lesions regardless of ErbB2 status. Here we show that clinically relevant doses of ionizing radiation (IR) induce cellular invasion of ErbB2-expressing breast cancer cells, such as SKBR3 and BT-474, as well as MCF10A cells transduced to express ErbB2. This effect is specific to ErbB2 expression, as ErbB2-negative breast cancer cells, such as MCF7 and T47D, do not invade following treatment with IR, nor do parental MCF10A cells or MCF10A cells overexpressing EGF receptor alone. Exposure of cells to X-rays leads to ErbB2 phosphorylation at Y877 in a dose- and time-dependent manner, and activates signaling pathways, including Src and PI3K/Akt. Inhibition of these pathways, as well as inactivation of IR-induced reactive oxygen species with the antioxidant N-acetylcysteine, prevented invasion. Activation of ErbB2-dependent signaling resulted in the upregulation of the transcription factor, FoxM1, a member of the forkhead family which has previously been shown to have a role in invasion, in part through transcriptional regulation of MMP2. Indeed, we have seen upregulation of MMP2 in irradiated ErbB2-expressing breast cancer cells, which is abolished when Src or ErbB2 is inhibited. Inhibition of FoxM1 by shRNA abrogated the increase in MMP2 level and prevented induction of invasion by IR, and overexpression of FoxM1 alone in MCF10A cells was sufficient to promote IR-induced invasion. Our data show that low level IR stimulates invasion of ErbB2-expressing breast cancer cells in a FoxM1-dependent manner. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-212. doi:1538-7445.AM2012-LB-212