Abstract 3433: Molecular regulation of RKIP, a tumor metastasis suppressor in breast cancer

Abstract

Abstract Breast cancer mortality is primarily due to metastasis to organs including bone, lungs, liver and brain. Tumor metastasis suppressors are metastasis inhibitors but do not affect the ability of the transformed cells to produce a tumor at the primary sites. Raf kinase inhibitory protein (RKIP) has been identified as a metastasis suppressor for a number of cancers including breast, prostate, liver, colon, skin, and nasopharyngeal carcinoma. RKIP overexpression in hepatoma, melanoma, and prostate metastatic cell lines diminished their invasiveness and motility in vitro. The molecular mechanism by which RKIP transcription is regulated in breast cancer is largely unknown. Interestingly, RKIP expression was highly and positively correlated with patient's metastasis-free survival after radiotherapy. Likewise, when RKIP was reduced in human prostate cancer cells, radiation-induced apoptosis was reduced in xenograft tumors. Moreover, RKIP expression levels have been induced upon chemotherapeutic drug treatment in human breast cancer cells, sensitizing the tumor cells to apoptosis. These studies indicate that chemotherapy and radiotherapy are more effective when RKIP is present in the metastatic cancer cells. Therefore, high RKIP levels are desirable to prevent metastasis of breast tumor cells and to sensitize tumor cells for chemotherapy. Our goal is to understand the mechanism by which RKIP is regulated in order to restore its levels. Previously, we have observed that let-7 negatively regulates two target genes, BACH1 and HMGA2 that promote breast cancer metastasis in a xenograft mouse model. Here we demonstrate that BACH1 and HMGA2 are themselves negative regulators of RKIP. Specifically, we have delineated molecular mechanisms by which BACH1 and HMGA2 inhibit RKIP expression in breast cancer cell lines using both luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays. We are also analyzing whether BACH1 and HMGA2 are dysregulated by chemotherapy in highly metastatic breast cancer cells and whether suppression of these RKIP regulators can potentiate sensitivity of the breast cancer cells to chemotherapy. These studies provide valuable mechanistic insights for potentiating chemotherapeutic sensitivity as well as potential biomarkers for metastatic breast cancer. 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 3433. doi:1538-7445.AM2012-3433