Abstract 3330: Overcoming drug resistance in triple negative breast cancer by targeting SMC1 and PARP.
Authors: Sushma Yadav, Zeynep Eroglu, Archana Sehrawat, George Somlo, Yate-Ching Yuan, Yogesh C. Awasthi, Sanjay Awasthi
Journal: Cancer Research (2013)

Abstract Triple-negative breast cancer (TNBC) is one of the hardest subtypes of breast cancer to treat due to the heterogeneity of the disease and absence of well defined molecular targets. SMC1 (structural maintenance of chromosome 1) is an ATPase known for its role in sister chromatid cohesion, DNA recombination and repair, and activation of the cell cycle checkpoints, and is a subunit of the cohesin complex. Emerging evidence has shown the role of cohesin in the formation and progression of various cancers including colon and lung cancer but the role of cohesin in breast cancer remains elusive. SMC1 has also been shown to bind with BRCA1 and is likely to be a component of the signaling network by which BRCA1 maintains genomic stability. While the only approved treatment for TNBC is chemotherapy, PARP (poly (ADP)-ribose polymerase) inhibitors have shown some activity in BRCA-mutated breast cancers, 80% of which are TNBC. Our data showed that SMC1 is differentially overexpressed both at RNA and protein level in a panel of TNBC cell lines (both basal and mesenchymal and two BRCA1-mutated) as compared to breast epithelial cells or hormone-receptor positive breast cancer cells, suggesting that the amplified product of this normal gene may play role in tumorigenesis in TNBC. In addition, our results showed that induced overexpression of SMC1 through transient transfection enhanced cell migration and anchorage independent growth while its suppression with siRNA reduced the ability of TNBC cells to metastasize. Increased expression of SMC1 also lead to an increase in the mesenchymal marker vimentin and decrease in the normal epithelial marker, E-cadherin. Immunocytochemical studies along with flow cytometry and cell fractionation showed the localization of SMC1 not only in the nucleus, but also in the plasma membrane. The knockdown of SMC1 by siRNA sensitized the TNBC cells towards the PARP inhibitor ABT-888 and IC50 was about three fold less than the ABT-888 alone. The cytotoxic effect of combination of SMC1 suppression and ABT-888 was also confirmed by the colony propagation assay. While PARP-inhibitors have shown the highest response rates in BRCA-mutated tumors in clinical trials, with addition of an SMC1 inhibitor, it may be possible to improve their response rate in BRCA wild type TNBC. Taken together, these studies report for the first time that SMC1 is overexpressed and involved in tumor migration of TNBC, and may be a novel target for use in combination with targeted agents and/or chemotherapy for treatment of this highly invasive breast cancer. Citation Format: Sushma Yadav, Zeynep Eroglu, Archana Sehrawat, George Somlo, Yate-Ching Yuan, Yogesh C. Awasthi, Sanjay Awasthi. Overcoming drug resistance in triple negative breast cancer by targeting SMC1 and PARP. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3330. doi:10.1158/1538-7445.AM2013-3330