Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition
Open Access
- 19 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (14), 3033-3045
- https://doi.org/10.1158/0008-5472.can-19-2739
Abstract
PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. 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 were 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 patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition.Keywords
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Funding Information
- Natural Science Foundation of China (81572890, 81672738, 81730077, 81772613, 81872370)
- Guangdong Science and Technology Department (2017B030314026)
- Science and Technology Program of Guangzhou (201704020095)
- Guangdong Introducing Innovative and Entrepreneurial Teams (2016ZT06S252)
- Sun Yat-Sen Memorial Hospital (Y201701)
- SU2C AACR (SU2C-AACR-DT0209)
This publication has 60 references indexed in Scilit:
- Combining a PI3K Inhibitor with a PARP Inhibitor Provides an Effective Therapy for BRCA1-Related Breast CancerCancer Discovery, 2012
- Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteinsTrends in Biochemical Sciences, 2011
- Death-Associated Protein Kinase 1 Phosphorylates Pin1 and Inhibits Its Prolyl Isomerase Activity and Cellular FunctionMolecular Cell, 2011
- Phosphorylation by Casein Kinase I Promotes the Turnover of the Mdm2 Oncoprotein via the SCFβ-TRCP Ubiquitin LigaseCancer Cell, 2010
- Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trialThe Lancet, 2010
- A comparison of BRCA1 nuclear localization with 14 DNA damage response proteins and domains: Identification of specific differences between BRCA1 and 53BP1 at DNA damage-induced fociCellular Signalling, 2010
- Cdk1 Participates in BRCA1-Dependent S Phase Checkpoint Control in Response to DNA DamageMolecular Cell, 2009
- Regulation of the p73 protein stability and degradationBiochemical and Biophysical Research Communications, 2005
- Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategyNature, 2005
- Mammalian DNA single-strand break repair: an X-ra(y)ted affairBioEssays, 2001