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Association of BRCA Mutations and BRCAness Status With Anticancer Drug Sensitivities in Triple-Negative Breast Cancer Cell Lines

Published:February 21, 2020DOI:https://doi.org/10.1016/j.jss.2019.12.040

      Abstract

      Background

      Many triple-negative breast cancers (TNBCs) show impaired breast cancer susceptibility gene I (BRCA1) function, called BRCAness. BRCAness tumors may show similar sensitivities to anticancer drugs as tumors with BRCA1 mutations. In this study, we investigated the association of BRCA mutations or BRCAness with drug sensitivities in TNBC.

      Methods

      BRCAness was evaluated as BRCA1-like scores, using multiplex ligation-dependent probe amplification in 12 TNBC cell lines, including four with mutations. Sensitivities to docetaxel, cisplatin, and epirubicin were compared with BRCA mutations and BRCA1-like scores. Cisplatin sensitivity was examined in BRCA1 knockdown Michigan Cancer Foundation-7 cell lines.

      Results

      Eight and four cell lines had characteristics of BRCAness and non-BRCAness, respectively. The 50% inhibitory concentration of docetaxel was higher in BRCA mutant and BRCAness cell lines than their counterparts. BRCA1-like scores showed a weak positive correlation with docetaxel sensitivity (r = 0.377; P = 0.039). Regarding cisplatin, scores were lower in BRCA mutants and BRCAness tumors than their counterparts. A negative correlation was found between BRCA1-like scores and cisplatin sensitivity (r = −0.407; P = 0.013). No differences were found for epirubicin. BRCA1 gene knockdown increased the cisplatin sensitivity of Michigan Cancer Foundation-7 cells.

      Conclusions

      BRCA1-like scores were associated with cisplatin sensitivity and docetaxel resistance. BRCA1-like score is hence a promising indicator for estimating drug sensitivities in TNBC.

      Keywords

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      References

        • Bauer K.R.
        • Brown M.
        • Cress R.D.
        • Parise C.A.
        • Caggiano V.
        Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry.
        Cancer. 2007; 109: 1721-1728
        • Criscitiello C.
        • Azim H.A.
        • Schouten P.C.
        • Linn S.C.
        • Sotiriou C.
        Understanding the biology of triple-negative breast cancer.
        Ann Oncol. 2012; 23: vi13-vi18
        • Dent R.
        • Trudeau M.
        • Pritchard K.I.
        • et al.
        Triple-negative breast cancer: clinical features and patterns of recurrence.
        Clin Cancer Res. 2007; 13: 4429-4434
        • Sorlie T.
        • Tibshirani R.
        • Parker J.
        • et al.
        Repeated observation of breast tumor subtypes in independent gene expression data sets.
        Proc Natl Acad Sci U S A. 2003; 100: 8418-8423
        • Sung M.
        • Giannakakou P.
        BRCA1 regulates microtubule dynamics and taxane-induced apoptotic cell signaling.
        Oncogene. 2014; 33: 1418-1428
        • Byrski T.
        • Gronwald J.
        • Huzarski T.
        • et al.
        Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers.
        Breast Cancer Res Treat. 2008; 108: 289-296
        • Kriege M.
        • Jager A.
        • Hooning J.M.
        • et al.
        The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers.
        Cancer. 2012; 118: 899-907
        • Lips E.H.
        • Mulder L.
        • Oonk A.
        • et al.
        Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers.
        Br J Cancer. 2013; 108: 2172-2177
        • Ishikawa T.
        • Narui K.
        • Takabe M.
        • et al.
        BRCAness is beneficial for indicating triple negative breast cancer patients resistant to taxane.
        Eur J Surg Oncol. 2016; 42: 999-1001
        • Lips E.H.
        • Debipersad R.D.
        • Scheerman C.E.
        • et al.
        BRCA1-mutated estrogen receptor-positive breast cancer shows BRCAness, suggesting sensitivity to drugs targeting homologous recombination deficiency.
        Clin Cancer Res. 2017; 23: 1236-1241
        • Lehmann B.D.
        • Bauer J.A.
        • Chen X.
        • et al.
        Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
        J Clin Invest. 2011; 121: 2750-2767
        • Byrski T.
        • Gronwald J.
        • Huzarski T.
        • et al.
        Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy.
        J Clin Oncol. 2010; 28: 375-379
        • Paluch-Shimon S.
        • Friedman E.
        • Berger R.
        • et al.
        Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers.
        Breast Cancer Res Treat. 2016; 157: 157-165
        • Lips E.H.
        • Laddach N.
        • Savola S.P.
        • et al.
        Quantitative copy number analysis by Multiplex Ligation-dependent Probe Amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness.
        Breast Cancer Res. 2011; 13: R107
        • Vos S.
        • Moelans C.B.
        • van Diest P.J.
        BRCA promoter methylation in sporadic versus BRCA germline mutation-related breast cancers.
        Breast Cancer Res. 2017; 19: 64
        • Oonk A.M.
        • Rijn Van, C.
        • Smits M.M.
        • et al.
        Clinical correlates of “BRCAness” in triple-negative breast cancer of patients receiving adjuvant chemotherapy.
        Ann Oncol. 2012; 23: 2301-2305
        • Mori H.
        • Kubo M.
        • Nishimura R.
        • et al.
        BRCAness as a biomarker for predicting prognosis and response to anthracycline-based adjuvant chemotherapy for patients with triple-negative breast cancer.
        PLoS One. 2016; 11: e0167016
        • Severson T.M.
        • Peeters J.
        • Majewski I.
        • et al.
        BRCA1-like signature in triple negative breast cancer: molecular and clinical characterization reveals subgroups with therapeutic potential.
        Mol Oncol. 2015; 9: 1528-1538
        • Wiederschain D.
        • Susan W.
        • Chen L.
        • et al.
        Single-vector inducible lentiviral RNAi system for oncology target validation.
        Cell Cycle. 2009; 8: 498-504
        • Bamford
        • et al.
        The Sanger Institute Catalogue of Somatic mutation in cancer website.
        (Available at:)
        http://www.sanger.au.uk/cosmic
        Date: 2014
        Date accessed: August 20, 2017
        • Bianchini G.
        • Balko J.M.
        • Mayer I.A.
        • Sanders M.E.
        • Gianni L.
        Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.
        Nat Rev Clin Oncol. 2016; 13: 674-690
        • Tookman L.A.
        • Browne A.K.
        • Connell C.M.
        • et al.
        RAD51 and BRCA2 enhance oncolytic adenovirus type 5 activity in ovarian cancer.
        Mol Cancer Res. 2016; 14: 44-55
        • Jacot W.
        • Thezenas S.
        • Senal R.
        • et al.
        BRCA1 promoter hypermethylation, 53BP1 protein expression and PARP-1 activity as biomarkers of DNA repair deficit in breast cancer.
        BMC Cancer. 2013; 13: 523
        • Ruscito I.
        • Dimitrova D.
        • Vasconcelos I.
        • et al.
        BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients—a study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD).
        Eur J Cancer. 2014; 50: 2090-2098
        • Joosse S.A.
        • van Beers E.H.
        • Tielen I.H.
        • et al.
        Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH.
        Breast Cancer Res Treat. 2009; 116: 479-489
        • Larsen M.J.
        • Kruse T.A.
        • Tan T.
        • et al.
        Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling.
        PLoS One. 2013; 8: e64268
        • Vollebergh M.A.
        • Lips E.H.
        • Nederlof P.M.
        • et al.
        An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients.
        Ann Oncol. 2011; 22: 1561-1570
        • Gross E.
        • Meul C.
        • Raab S.
        • et al.
        Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers.
        Br J Cancer. 2013; 109: 2347-2355
        • Telli M.L.
        • Timms K.M.
        • Reid J.
        • et al.
        Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer.
        Clin Cancer Res. 2016; 22: 3764-3773
        • Graeser M.
        • McCarthy A.
        • Lord C.J.
        • et al.
        A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer.
        Clin Cancer Res. 2010; 16: 6159-6168
        • Tassone P.
        • Tagliaferri P.
        • Perricelli A.
        • et al.
        BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells.
        Br J Cancer. 2003; 88: 1285-1291
        • Tutt A.
        • et al.
        Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial.
        Nat Med. 2018; 24: 628-637
        • Turner N.
        • Tutt A.
        • Ashworth A.
        Hallmarks of 'BRCAness' in sporadic cancers.
        Nat Rev Cancer. 2004; 4: 814-819
        • Vollebergh M.A.
        • Lips E.H.
        • Nederlof P.M.
        • et al.
        Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.
        Breast Cancer Res. 2014; 16: R47