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?-hCG-induced mutant BRCA1 ignites drug resistance in susceptible breast tissue.

ABSTRACT: ?-hCG expression in breast cancer is highly controversial with reports supporting both protective and tumorigenic effects. It has also been reported that risk of breast cancer at an early age is increased with full-term pregnancies if a woman is a BRCA1 mutation carrier. We have already demonstrated that BRCA1-defective cells express high levels of ?-hCG and that when BRCA1 is restored, ?-hCG level is reduced. Also, BRCA1 can bind to the promoter and reduce the levels of ?-hCG. ?-hCG induces tumorigenicity in BRCA1-defective cells by directly binding to TGFBRII and induces TGFBRII-mediated cell proliferation. In this study, we analyzed the mechanism of action of ?-hCG on BRCA1 expression and its influence on drug sensitivity in breast cancer cells. We demonstrate that ?-hCG induces mutant BRCA1 protein expression in BRCA1 mutant cells; however, in BRCA1 wild-type cells, ?-hCG reduced wild-type BRCA1 protein expression. Transcriptionally, ?-hCG could induce Slug/LSD1-mediated repression of wild-type and mutant BRCA1 messenger RNA levels. However, ?-hCG induces HSP90-mediated stabilization of mutant BRCA1 and hence the overexpression of mutant BRCA1 protein, resulting in partial restoration of homologous recombination repair of damaged DNA. This contributes to drug resistance to HSP90 inhibitor 17AAG in BRCA1-defective cancer cells. A combination of HSP90 inhibitor and TGFBRII inhibitor has shown to sensitize ?-hCG expressing BRCA1-defective breast cancers to cell death. Targeting the ?-hCG-HSP90-TGFBRII axis could prove an effective treatment strategy for BRCA1-mutated breast tumors.

SUBMITTER: Sengodan SK

PROVIDER: S-EPMC7175285 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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β-hCG-induced mutant BRCA1 ignites drug resistance in susceptible breast tissue.

Sengodan Satheesh Kumar SK Hemalatha Sreelatha K SK Nadhan Revathy R Somanathan Thara T Mathew Arun Peter AP Chil Arkadiusz A Kopczynski Janusz J Nair Rakesh Sathish RS Kumar Jerald Mahesh JM Srinivas Priya P

Carcinogenesis 20191101 11

β-hCG expression in breast cancer is highly controversial with reports supporting both protective and tumorigenic effects. It has also been reported that risk of breast cancer at an early age is increased with full-term pregnancies if a woman is a BRCA1 mutation carrier. We have already demonstrated that BRCA1-defective cells express high levels of β-hCG and that when BRCA1 is restored, β-hCG level is reduced. Also, BRCA1 can bind to the promoter and reduce the levels of β-hCG. β-hCG induces tum ...[more]

PMID: 30963174

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Project description:BackgroundLittle is known about mechanisms of resistance to poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure.Patients and methodsWe obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARPi or platinum chemotherapy. Whole exome sequencing was carried out on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was carried out for functional assessment of intact homologous recombination (HR).ResultsPre- and post-resistance tumor samples were sequenced from eight patients (four with BRCA1 and four with BRCA2 mutation; four treated with PARPi and four with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore HR through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of HR. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy.ConclusionsGenomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in four of eight patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.

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?-hCG-induced mutant BRCA1 ignites drug resistance in susceptible breast tissue.

Publications

β-hCG-induced mutant BRCA1 ignites drug resistance in susceptible breast tissue.

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