Abstract
Abstract Previous array comparative genomic hybridization (aCGH) studies in our lab have shown that chromosomal gains on 17q22-24.2 are associated with invasion when detected in duct carcinoma in situ (DCIS) and nodal metastasis when detected in invasive duct carcinoma (IDC). Of nine candidate genes identified within this region, MSI2 was selected for further study. MSI2 is a Musashi family RNA binding protein that translationally regulates target mRNAs. RNAi screens have indicated that MSI2 down regulation impairs hematopoietic stem cell repopulation. Other studies implicate its role in leukemia and colon cancer. Downstream targets of the MSI2 homologue MSI1, have shown a strong correlation with cancer related processes through their roles in cell cycle modulation, proliferation, differentiation, and apoptosis. MSI1 has also been shown to modulate WNT and Notch signaling through its interactions with the Notch inhibitor NUMB and the WNT antagonist DKK3. Invasion, migration, and proliferation assays were carried out in the breast cancer cell lines MDA231 and MCF7 over-expressing MSI2. These cell lines were also transfected with the TOPflash TCF reporter plasmid to investigate the effect of MSI2 over-expression on WNT signaling. To investigate the effects of WNT signaling on MSI2, MDA231 cell lines were treated with the human WNT agonist WNT-3a and MSI2 levels were quantified via western blotting. RNA immunoprecipitation was performed to analyze the downstream targets of MSI2. To investigate the role of MSI2 in breast stem and progenitor cell populations, cell lines were grown as non-adherent mammospheres. MSI2 RNA levels in mammospheres were compared via qRT-PCR. Lastly, the expression of a panel of stem cell markers was compared between cells over-expressing MSI2 and GFP controls via qRT-PCR. Our results show MSI2 over-expressing MCF7 and MDA231 cells have increased levels of proliferation, migration, and invasion. MSI2 over-expressing cells also up-regulate several putative stem cell markers including Epithelial Cell Adhesion Molecule (EpCAM), CD133, and Aldehyde Dehydrogenase. MSI2 levels are significantly enhanced in mammosphere culture and MSI2 over-expressing cells have demonstrated an increase in mammosphere forming capabilities. We believe MSI2 plays an important role in breast cancer through its modulation of RNA translation and subsequent regulation of WNT signaling and stem cell biology. MSI2 represents a promising therapeutic target which could be used to block breast cancer invasion and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2356. doi:10.1158/1538-7445.AM2011-2356
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