. 2015 Aug;35(15).
doi: 10.1038/onc.2015.287.

Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer

D Merino 1 S W Lok 1 J E Visvader 1 G J Lindeman 1 
  • PMID: 26257067
  •     112 References
  •     35 citations


The last three decades have seen significant progress in our understanding of the role of the pro-survival protein BCL-2 and its family members in apoptosis and cancer. BCL-2 and other pro-survival family members including Mcl-1 and BCL-XL have been shown to have a key role in keeping pro-apoptotic 'effector' proteins BAK and BAX in check. They also neutralize a group of 'sensor' proteins (such as BIM), which are triggered by cytotoxic stimuli such as chemotherapy. BCL-2 proteins therefore have a central role as guardians against apoptosis, helping cancer cells to evade cell death. More recently, an increasing number of BH3 mimetics, which bind and neutralize BCL-2 and/or its pro-survival relatives, have been developed. The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients. As BCL-2 is overexpressed in ~75% of breast cancer, there has been growing interest in determining whether this new class of drug could show similar promise in breast cancer. This review summarizes our current understanding of the role of BCL-2 and its family members in mammary gland development and breast cancer, recent progress in the development of new BH3 mimetics as well as their potential for targeting estrogen receptor-positive breast cancer.

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Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer.
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The p53 positive Bcl-2 negative phenotype is an independent marker of prognosis in breast cancer.
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Int J Cancer, 2006 Dec 26; 120(6). PMID: 17187363
Bax regulates c-Myc-induced mammary tumour apoptosis but not proliferation in MMTV-c-myc transgenic mice.
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Br J Cancer, 2004 Sep 09; 91(7). PMID: 15354213    Free PMC article.
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ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL.
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Knockdown of miR-221 promotes the cisplatin-inducing apoptosis by targeting the BIM-Bax/Bak axis in breast cancer.
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Tumour Biol, 2015 Oct 28; 37(4). PMID: 26503209
All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation.
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Sci Rep, 2016 Mar 05; 6. PMID: 26935534    Free PMC article.
Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma.
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Int J Nanomedicine, 2016 Apr 05; 11. PMID: 27042063    Free PMC article.
KSP inhibitor SB743921 inhibits growth and induces apoptosis of breast cancer cells by regulating p53, Bcl-2, and DTL.
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Anticancer Drugs, 2016 Jul 06; 27(9). PMID: 27379929    Free PMC article.
Decreased TRPM7 inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway.
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Oncotarget, 2016 Sep 24; 7(45). PMID: 27662662    Free PMC article.
Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.
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Mol Cancer Res, 2017 Jan 01; 15(3). PMID: 28039357    Free PMC article.
Profile of venetoclax and its potential in the context of treatment of relapsed or refractory chronic lymphocytic leukemia.
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Onco Targets Ther, 2017 Feb 23; 10. PMID: 28223822    Free PMC article.
Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2.
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PLoS One, 2017 Mar 17; 12(3). PMID: 28301598    Free PMC article.
Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action.
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Age-associated prognostic and predictive biomarkers in patients with breast cancer.
Markéta Kolečková, Zdeněk Kolář, +2 authors, Radek Trojanec.
Oncol Lett, 2017 Jun 11; 13(6). PMID: 28599421    Free PMC article.
FGFR2-Driven Signaling Counteracts Tamoxifen Effect on ERα-Positive Breast Cancer Cells.
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Neoplasia, 2017 Sep 05; 19(10). PMID: 28869838    Free PMC article.
Cat Mammary Tumors: Genetic Models for the Human Counterpart.
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Vet Sci, 2016 Aug 16; 3(3). PMID: 29056725    Free PMC article.
Overexpression of CCDC34 in colorectal cancer and its involvement in tumor growth, apoptosis and invasion.
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Mol Med Rep, 2017 Nov 09; 17(1). PMID: 29115580    Free PMC article.
A hederagenin saponin isolated from Clematis ganpiniana induces apoptosis in breast cancer cells via the mitochondrial pathway.
Lin Cheng, Liang Shi, +6 authors, Qiang Ding.
Oncol Lett, 2018 Feb 13; 15(2). PMID: 29434869    Free PMC article.
Correlation of expression levels of caspase-3 and Bcl-2 in alveolar lavage fluid in neonatal respiratory distress syndrome and prognosis.
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Exp Ther Med, 2018 Feb 20; 15(3). PMID: 29456694    Free PMC article.
Pharmacological targets of breast cancer stem cells: a review.
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Targeting BCL-2 in Hematologic Malignancies.
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Target Oncol, 2018 Mar 10; 13(3). PMID: 29520705
CMPD1 inhibited human gastric cancer cell proliferation by inducing apoptosis and G2/M cell cycle arrest.
Yu Li, Depeng Zhang, +4 authors, Zishu Wang.
Biol Res, 2018 Apr 18; 51(1). PMID: 29661232    Free PMC article.
Emerging ways to treat breast cancer: will promises be met?
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Paip1 Indicated Poor Prognosis in Cervical Cancer and Promoted Cervical Carcinogenesis.
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Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers.
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Identification of prognostic biomarkers for malignant melanoma using microarray datasets.
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ER+ metastatic breast cancer: past, present, and a prescription for an apoptosis-targeted future.
Brett Rozeboom, Nandini Dey, Pradip De.
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Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity.
Claudia Riccardi, Domenica Musumeci, +3 authors, Daniela Montesarchio.
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Identification of molecular features necessary for selective inhibition of B cell lymphoma proteins using machine learning techniques.
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MicroRNA-148b enhances the radiosensitivity of B-cell lymphoma cells by targeting Bcl-w to promote apoptosis.
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The regulatory protein GADD34 inhibits TRAIL-induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells.
Peiying Song, Songpeng Yang, +5 authors, Yangfu Jiang.
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Rhazyaminine from Rhazya stricta Inhibits Metastasis and Induces Apoptosis by Downregulating Bcl-2 Gene in MCF7 Cell Line.
Waqas Iqbal, Saleh Alkarim, +4 authors, Kulvinder S Saini.
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Deguelin induces apoptosis in colorectal cancer cells by activating the p38 MAPK pathway.
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Cancer Manag Res, 2018 Dec 28; 11. PMID: 30588113    Free PMC article.
Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin.
Javier Menéndez-Menéndez, Francisco Hermida-Prado, +7 authors, Carlos Martínez-Campa.
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microRNA-139-3p Inhibits Malignant Behaviors of Laryngeal Cancer Cells via the KDM5B/SOX2 Axis and the Wnt/β-Catenin Pathway.
Yifei Ma, Zili Chen, Guodong Yu.
Cancer Manag Res, 2020 Oct 17; 12. PMID: 33061611    Free PMC article.
Induction of Redox-Mediated Cell Death in ER-Positive and ER-Negative Breast Cancer Cells by a Copper(II)-Phenolate Complex: An In Vitro and In Silico Study.
Vaiyapuri Subbarayan Periasamy, Anvarbatcha Riyasdeen, +4 authors, Mohammad Abdulkader Akbarsha.
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Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer.
Francesca De Amicis, Adele Chimento, +3 authors, Vincenzo Pezzi.
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BCL-2 Inhibitor Venetoclax Induces Autophagy-Associated Cell Death, Cell Cycle Arrest, and Apoptosis in Human Breast Cancer Cells.
Ali Alhoshani, Fahad O Alatawi, +7 authors, Hesham M Korashy.
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Targeted Neoadjuvant Therapies in HR+/HER2-Breast Cancers: Challenges for Improving pCR.
Nandini Dey, Jennifer Aske, Pradip De.
Cancers (Basel), 2021 Feb 04; 13(3). PMID: 33530335    Free PMC article.