Abstract 3312: Targeting Notch signaling to abrogate the increase in breast cancer stem cells induced by hypoxia

Abstract

Abstract There is increasing evidence from our lab and others supporting the “cancer stem cell” hypothesis in breast cancer, which deems that tumors are driven a small population of cells exhibiting stem cell properties. These cancer stem/progenitor cells may also be responsible for mediating tumor metastasis and resistance to cancer treatments. Recently, several new cancer therapies targeting tumor angiogenesis have been developed and validated in clinical trials. However, clinical practice has revealed that these therapies ultimately result in drug resistance and do not prolong patient survival by more than a few months. It has been reported that these angiogenesis inhibitors promote tumor invasiveness and metastasis in rodent breast cancer models. We have used in vitro and in vivo assays to study the role of hypoxia in regulating mammary cancer stem cells. We have shown that breast tumor stem cell population increases in response to hypoxia in vitro and in tumors from anti-angiogenic treated mice. We hypothesize that this leads to increased tumor aggressiveness and may explain the resistance to these drugs seen in patients. In vivo, both sunitinib and bevacizumab treatment increased intratumoral hypoxia as well as the percentage of cells expressing ALDH as assessed by the Aldefluor assay in SUM-159 and MDA-MB-231 breast cancer xenografts in NOD/SCID mice. In addition, tumor cells obtained from sunitinib treated mice exhibit enhanced growth of secondary tumors in NOD/SCID mice, further supporting an increase in the tumor stem cell population. We also demonstrate that hypoxia (1-2% oxygen) enriches for stem cells by at least 2 fold in several breast cancer cell lines grown in vitro. Utilizing siRNA, we identified that HIF1a is required for the increased cancer stem cell population following hypoxia treatment. We next tested whether a gamma secretase inhibitor (GSI) can block hypoxia's ability to increase the cancer stem cell population since HIF1a is reported to activate the Notch signaling pathway, and this pathway is known to regulate stem cell self renewal. Treatment of cells with the GSI completely abrogated the increase in ALDH+ cells under hypoxic conditions. We are now testing the ability of GSIs to block the increase in CSCs seen in mice treated with anti-angiogenic drugs. This study may reveal that therapies targeting tumor angiogenesis should be combined with GSI treatments targeting the cancer stem cell population. 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 3312. doi:1538-7445.AM2012-3312