Abstract
Abstract The PTEN and p53 tumor suppressor genes, frequently inactivated in human breast cancers have been shown to be regulators of normal and malignant breast stem cell self-renewal. In addition, inactivation of tumor suppressors in preneoplastic lesions are implicated in tumor progression from ductal situ in carcinoma (DCIS) to invasive ductal carcinoma. To determine the relationship between stem cell self-renewal and carcinogenesis, we examined the effects of PTEN and p53 knockdown on normal mammary epithelial cells obtained from reduction mammoplasties, as well as in the non-transformed mammary cell line MCF10A. Simultaneous knockdown of PTEN and p53 in normal mammary epithelial cells generated hyperplastic and DCIS-like lesions when these cells were transplanted into the humanized mammary fat pads of NOD/SCID mice. In MCF10A cells knockdown of PTEN and p53 synergized to expand the stem cell compartment transforming these cells and generating highly metastatic tumors in NOD/SCID mice. Stem cell expansion was driven by activation of an inflammatory loop involving both IL-6 and TGF-b. This inflammatory loop was mediated by both AKT/b-Catenin and Stat3/NF-kB pathways. Conversely collective inhibition of these pathways including TGF-b, IL-6 and Wnt/b-Catenin and Stat3/NF-kB was necessary to revert back this stem cell phenotype. This may suggest that synergistic activity of these pathways may contribute to the expansion and transformation of mammary stem cells. The expanded cancer stem cells were highly metastatic and invasive and displayed properties of EMT. The IL6-R antibody tocilizumab blocked this loop resulting in a reduction of CSCs and thus inhibiting tumor growth in mouse xenografts. These studies suggest that loss of PTEN and p53 transforms mammary epithelial cells by activating an inflammatory loop mediated by IL-6 and TGF-b, generating CSCs with an EMT phenotype. Since CSCs drive tumor growth and metastasis, targeting the self-renewal by interfering with this CSC, inflammatory loop represents a rational strategy for breast cancer prevention and therapy. 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 3349. doi:1538-7445.AM2012-3349
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