Inactivation of the prolyl isomerase Pin1 sensitizes BRCA1-proficient breast cancer to PARP inhibition.

PARP inhibitor monotherapies effectively treat breast, ovary, prostate, and pancreatic cancer patients with BRCA1 mutations, but not the more frequent BRCA-wildtype cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we report here that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by post-phosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, which is catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilized BRCA1 by preventing ubiquitination of BRCA1 at Lys1037. Loss of Pin1 or introduction of a BRCA1 mutant refractory to Pin1 binding decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells was modestly repressed by Olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB 231 xenografts and triple-negative breast cancer PDX, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to Olaparib. Together our study reveals that Pin1 inhibition with widely used ATRA acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition.