Abstract P2-06-02: The condensin core subunit, SMC2 (structural maintenance of chromosomes 2), is necessary for the growth and genomic stability of triple negative breast cancer cells

Abstract

Abstract Chromosomal instability (CIN) is a characteristic of many cancers that contributes to a tumor cell’saccumulation of genetic defects including mutations, copy number alterations, and aneuploidy.By promoting intratumoral heterogeneity and genetic diversity, CIN can confer a selectiveadvantage to tumor cells and promote cancer progression. Triple Negative Breast Cancers(TNBCs) typically have high rates of CIN, and this contributes to disease aggressiveness andpoor patient outcomes. While basal levels of CIN contribute to cancer progression, CIN can beelevated to intolerable levels to induce mitotic catastrophe or cell death that occurs during, orimmediately following, mitosis. Discovering proteins necessary for cells to maintain basal levelsof CIN that can then be leveraged to induce mitotic catastrophe should reveal vulnerabilities thatare therapeutically targetable. In this regard, we have identified Structural Maintenance ofChromosomes 2 (SMC2) as a modulator of CIN in TNBC. SMC2 is a core member of condensin,a complex which is largely known for its role in maintaining chromosome architecture. SMC2 hasalso recently been implicated in the regulation of transcription, suggesting that this enzyme maylie at the interface of transcription and chromatin configuration. We hypothesize that TNBC cellsrely on SMC2 to control CIN through two routes: chromatin organization and transcription ofoncogenes and cell identity genes. To begin to test this hypothesis, we assessed the impact ofSMC2 silencing on TNBC cell growth in multiple cell lines. While reducing SMC2 levels initiallyincreases proliferation, SMC2 is required for long term TNBC cell viability and proper progressionthrough the cell cycle. Shortly following SMC2 suppression, TNBC cells display an increase inCIN phenotypes including multinucleation, micronucleation, and dysmorphic nucleation, as wellas DNA double strand breaks. These defects accumulate to an excessive level that ultimatelyinduces cell death. Notably, SMC2 is overexpressed in a subset of TNBC patient tumors and thisoverexpression is associated with an increased number of mutations, copy number alterations,and aneuploidy, as well as worse patient outcomes. Together, these results indicate that SMC2regulates CIN in TNBC. Given its function as an ATPase, we conclude that SMC2 is a potentialtarget for therapeutic development for the treatment of TNBC, a disease with limited therapeuticoptions. Current studies are focused on discovering the mechanisms by which SMC2 regulatesCIN in TNBC. Citation Format: Jessica Ventura, Bryan Webb, Ruth Keri. The condensin core subunit, SMC2 (structural maintenance of chromosomes 2), is necessary for the growth and genomic stability of triple negative breast cancer cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-06-02.