Abstract C76: FoxM1 inhibition sensitized BRCA-proficient triple-negative breast cancer to PARP inhibition.

Abstract

Abstract Breast cancer cells with mutations in breast cancer-associated 1 (BRCA1) or BRCA2 have defects in the homologous recombination (HR) DNA repair pathway and this confers sensitivity to inhibitors of poly (ADP) ribose polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. The transcription factor Forkhead box M1 (FoxM1) is a key regulator of cell proliferation and is overexpressed in many forms of primary cancers, leading to uncontrolled cell division and genomic instability. FoxM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Our results revealed that triple-negative breast cancer (TNBC) cell lines depleted in FoxM1 levels by small interfering RNA transfection display increase DNA damage, as evidence by activation of checkpoint kinase 2 (Chk2) and phosphorylation of histone H2AX. These results shows a role for FoxM1 in the transcriptional response during DNA damage/checkpoint signaling and we hypothesized that FoxM1 inhibition would result in HR impairment and subsequent sensitization to PARP inhibitor. We found that knockdown of FoxM1 led to sensitization to AZD2281, PARP inhibitor, in MDA-MB-231 (BRCA-wild-type) and MDA-MB-436 (BRCA-mutated) TNBC cells. Combined PARP and FoxM1 inhibition had a synergistic anti-proliferative effect on BRCA1-defective and BRCA-proficient TNBC cell lines in vitro. Furthermore, the combination treatment of AZD2281 and thiostrepton (FoxM1 inhibitor) increased DNA repair-related gene expression such as H2AX, chk1, chk2 and p53 and downregulated BRCA2 expression in TNBC cell lines. Here, we show that depletion or inhibition of FoxM1 compromises the ability of cells to repair DNA by HR and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine FoxM1 and PARP inhibitors. Therefore, this combination may be effective for treating both BRCA1-defective and BRCA-proficient TNBC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C76. Citation Format: Jun Woo Lee, Kyung-Min Lee, Wonshik Han. FoxM1 inhibition sensitized BRCA-proficient triple-negative breast cancer to PARP inhibition. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C76.