BRCA2-Deficient Sarcomatoid Mammary Tumors Exhibit Multidrug Resistance

Jaspers, Janneke E.; Sol, Wendy; Kersbergen, Ariena; Schlicker, Andreas; Guyader, Charlotte; Xu, Guotai; Wessels, Lodewyk; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

doi:10.1158/0008-5472.can-14-0839

Cited by 50 publications

(41 citation statements)

References 52 publications

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“…To determine whether overexpression of miR-493-5p could be a possible mechanism of acquired resistance in BRCA2 -mutated cancers, we utilized the unique genetically engineered mouse (GEM) KB2P mouse model for Brca2 -deficient breast cancer (Jaspers et al, 2015; Jonkers et al, 2001). This model harbors large intragenic deletion in Brca2 ; therefore, acquired resistance to PARPis in this model cannot occur via secondary Brca2 mutations.…”

Section: Resultsmentioning

confidence: 99%

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

et al. 2018

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SUMMARY BRCA1/2-mutated ovarian cancers (OCs) are defective in homologous recombination repair (HRR) of double-strand breaks (DSBs) and thereby sensitive to platinum and PARP inhibitors (PARPis). Multiple PARPis have recently received US Food and Drug Administration (FDA) approval for treatment of OCs, and resistance to PARPis is a major clinical problem. Utilizing primary and recurrent BRCA1/2-mutated carcinomas from OC patients, patient-derived lines, and an in vivo BRCA2-mutated mouse model, we identified a microRNA, miR-493-5p, that induced platinum/PARPi resistance exclusively in BRCA2-mutated carcinomas. However, in contrast to the most prevalent resistance mechanisms in BRCA mutant carcinomas, miR-493-5p did not restore HRR. Expression of miR-493-5p in BRCA2-mutated/depleted cells reduced levels of nucleases and other factors involved in maintaining genomic stability. This resulted in relatively stable replication forks, diminished single-strand annealing of DSBs, and increased R-loop formation. We conclude that impact of miR-493-5p on multiple pathways pertinent to genome stability cumulatively causes PARPi/platinum resistance in BRCA2 mutant carcinomas.

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Section: Resultsmentioning

confidence: 99%

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

et al. 2018

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“…In addition, we found elevated ABCB1 expression in human EMT-like TNBCs with a claudin-low gene expression pattern, suggesting that human BRCA1-deficient MBCs also may display reduced sensitivity to olaparib as a result of Pgpmediated drug efflux. Interestingly, increased Pgp expression was also associated with olaparib resistance in BRCA2-deficient carcinosarcomas from K14cre;Brca2 F/F ;Trp53 F/F mice (31). However, in a KB1P-MET carcinosarcoma expressing low levels of Pgp, unresponsiveness to PARP inhibition could not be explained by drug efflux.…”

Section: Discussionmentioning

confidence: 97%

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Henneman

Miltenburg

Michalak

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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107

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Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. resistance | mouse model | breast cancer | BRCA1 | PARP P oly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic strategy for targeting homologous recombination (HR)-deficient tumors, such as breast cancer 1 (BRCA1)-mutated cancers (1). Indeed, clinical phase I and phase II trials have shown potent anticancer activity of small molecule inhibitors of PARP, such as olaparib, in patients with BRCA1-associated breast cancer (2, 3). However, it remains to be established whether different breast cancer subtypes in BRCA1 mutation carriers respond equally to PARP inhibition. Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4-7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9). More than 60% of MBCs have BRCA1 promoter methylation, raising the question whether these tumors can be effectively targeted by using PARP inhibitors (10). To address this issue in an experimentally controlled setting, we set out to generate a genetically engineered mouse model (GEMM) of BRCA1-deficient MBC by inducing EMT via MET overexpression in a previously established GEMM of BRCA1-mutated breast cancer. We report that EMT is associated with olaparib resistance and can be effectively bypassed by administration of AZD2461, a PARP inhibitor with low affinity for the P-glycoprotein (Pgp) drug efflux transporter. Results Development of a GEMM-ESC Strategy for Mouse Mammary TumorModels. GEMMs have the potential to capture the cell-intrinsic and cell-extrinsic factors that drive de novo tumor formation, making them exceptionally valuable for cancer research (11). To speed up the development of novel multiallele GEMMs of human cancer, we...

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“…It is hence possible that a defective spindle assembly checkpoint associated with BRCA2 inactivation causes an impaired efficacy of docetaxel. In addition, a link between BRCA2 inactivation and multidrug resistance has been reported 39 . Since docetaxel is a substrate for multidrug resistance transporters such as P-glycoprotein, docetaxel efflux may be enhanced in BRCA2 -mutated prostate cancers.…”

Section: Discussionmentioning

confidence: 99%

Mutations in BRCA2 and taxane resistance in prostate cancer

Nientiedt

Heller

Endris

et al. 2017

Sci Rep

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Mutations in BRCA1 or BRCA2 define a subset of prostate cancer patients. Herein, we address the question whether BRCA1/2 mutations have a predictive impact on chemotherapy with docetaxel, a widely used drug in patients with metastatic castration resistant prostate cancer (mCRPC). Fifty-three men treated with docetaxel for mCRPC were tested for somatic BRCA1/2 mutations of the primary tumor. In a subgroup of patients, BRCA1/2 protein expression was tested as a potential surrogate marker for BRCA1/2 inactivation. Eight of 53 patients (15.1%) harbored a deleterious BRCA2 mutation. No BRCA1 mutation was found. Patients with a BRCA2 mutation showed a response rate of 25% to docetaxel in comparison to 71.1% in men with wildtype BRCA2 (p = 0.019). While the time to develop castration resistance was similar in both subgroups, the overall survival was significantly shorter in patients harboring a BRCA2 mutation. No correlation between the BRCA1/2 protein expression and the response to docetaxel was found. While the presence of a BRCA2 mutation does not preclude a response to docetaxel, there is overall a significant correlation between BRCA2 inactivation and a poor response rate. Our results suggest that a close oncological monitoring of patients with BRCA2 mutations for taxane resistance is warranted.

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BRCA2-Deficient Sarcomatoid Mammary Tumors Exhibit Multidrug Resistance

Cited by 50 publications

References 52 publications

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Mutations in BRCA2 and taxane resistance in prostate cancer

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