Abstract P4-06-06: RNAi screen of the breast cancer genome identifies KIF14 and TLN1 as genes that modulate chemosensitivity in breast cancer

Abstract We conducted a RNA-interference screen for genes whose loss-of-function enhanced doxorubicin and docetaxel chemosensitivity in a “triple-negative,” estrogen receptor negative, progesterone receptor negative, and Her2 negative (ER− PR− Her2−) breast cancer cell line, MDA-MB-231. From ranking chemosensitivity of 334 short-hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 134 genes with known somatic mutations in breast cancer), we focused on two genes, kinesin family member 14 (KIF14) and talin (TLN1) that not only enhanced chemosensitivity but also have oncogenic annotations. KIF14 has robust expression in breast cancer cells compared to normal mammary cells. TLN1 expression is important for migration of breast cancer cells. In TLN1-deficient cells, CK19 and ZO-1 are upregulated while CK14 and snail are downregulated, suggesting that TLN1 is important for the maintenance of epithelial-mesenchymal transition in MDA-MB-231 cells. KIF14 and TLN1 loss-of-function also enhanced chemosensitivity in 3 other triple negative breast cancer cell lines (HCC1937, HCC38, and Hs578T) but not in normal human mammary epithelial cells (HMECs). Examining protein-protein-interaction networks, we identified RIP2 as a target whose inhibition via SB203580 or PP2 can further enhance chemosensitization in KIF14-deficient cells. Knock-down of a number of other known protein-protein interaction partners of KIF14 and TLN1, including FAK, CIT, ARRB2, PSTPiP1, PRC1, SVIL, ITGA2B, ITGB3, VCL and PXN, do not significantly alter doxorubicin or docetaxel chemosensitivity in MDA-MB-231 cells. Mammary fat pad xenografts of KIF14- and TLN1- deficient MDA-MB-231 cells into NOD/SCID mice demonstrated significantly less tumor mass compared to control MDA-MB-231 cells after chemotherapy. Expressions of KIF14 and TLN1 from breast cancer expression arrays improve prognostic predictions compared to clinicopathological features alone. In summary, screenings for therapeutic targets using chemotherapy and genes with known somatic mutations in breast cancer not only provide a rational targeted screen, but also present possible up-front novel treatment combinations for patients with triple negative breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-06.