Abstract A055: A novel cell growth control pathway repressed by the oncogene TBX2 in breast cancer cells

Abstract

Abstract Purpose: To identify a therapeutic target downstream of TBX2 which may be used to treat this aggressive subset of breast cancers T-box 2 (TBX2) is a transcriptional repressor known to drive breast cancer proliferation. It is known to switch off a number of key cell cycle regulatory molecules such as p21WAF1 and p14ARF. A breast cancer Disease Specific Array identified >700 potential TBX2 regulated genes. We have validated one particular target, Cystatin 6 (CST6), to be consistently repressed by TBX2 in a panel of breast cancer cell lines. CST6 is a putative breast tumor suppressor and we observe that exogenous expression of CST6 resulted in cell death of breast cancer cells but not in non-tumorigenic breast cell lines. Mechanistically, we show that TBX2 transcriptionally represses CST6 in an EGR-1 dependent manner rather than through direct CST6 promoter binding. CST6 is a cysteine protease inhibitor known to repress several members of Clan CA (papain family) and Legumain (LGMN, an asparginyl endopeptidase from the Clan CD family). LGMN has previously been reported to be highly expressed in breast cancers compared to normal breast tissue. Through a range of genomic approaches we showed that LGMN was responsible for driving the proliferation of breast cancer cell lines. Consequently, knockdown of LGMN by siRNA resulted in cell death in breast cancer cell lines overexpressing TBX2. We are in the process of generating small molecule inhibitors against LGMN. Preliminary studies have shown promise with growth inhibitory effects on breast cancer cells but not in non-tumorigenic MCF10A breast cells. LGMN inhibitors may be useful for targeted treatment for breast and other tumors types showing high levels of LGMN expression where it is known to play roles in control of ECM remodeling/turnover, tumor growth and in the development of metastases. LGMN is also known to process and activate a number of downstream oncogenic proteins and we show that one of these proteins, matrix metalloproteinase-2 (MMP2), may contribute to the aggressive traits of LGMN-expressing breast cancer cells. Conclusions: We have determined a proliferative/invasive pathway employed by breast cancer cells and identified a protein downstream ‘LGMN’ which may be therapeutically targeted to prevent oncogenesis in a subset of breast cancers. Citation Format: Zenobia Carmel D'Costa, Catherine A. Higgins, Richard Williams, Paul B. Mullan. A novel cell growth control pathway repressed by the oncogene TBX2 in breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A055.