Stumbling Blocks on the Path to Personalized Medicine in Breast Cancer: The Case of PARP Inhibitors for <i>BRCA1/2</i>-Associated Cancers

Balmañà, Judith; Domchek, Susan M.; Tutt, Andrew; Garber, Judy E.

doi:10.1158/2159-8274.cd-11-0048

Cited by 42 publications

(23 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have highlighted the utility of combining DNAdamaging chemotherapy with PARP inhibition (30)(31)(32). PARP inhibitors were initially evaluated in BRCA-deficient breast cancers based on the predicted "synthetic lethality" between PARPdependent largely single-strand break repair and BRCA-associated DSB repair (31).…”

Section: Discussionmentioning

confidence: 99%

BAL1 and Its Partner E3 Ligase, BBAP, Link Poly(ADP-Ribose) Activation, Ubiquitylation, and Double-Strand DNA Repair Independent of ATM, MDC1, and RNF8

Yan

Zhu

et al. 2013

Molecular and Cellular Biology

102

115

View full text Add to dashboard Cite

The BAL1 macrodomain-containing protein and its partner E3 ligase, BBAP, are overexpressed in chemotherapy-resistant lymphomas. BBAP selectively ubiquitylates histone H4 and indirectly promotes early 53BP1 recruitment to DNA damage sites. However, neither BBAP nor BAL1 has been directly associated with a DNA damage response (DDR), and the function of BAL1 remains undefined. Herein, we describe a direct link between rapid and short-lived poly(ADP-ribose) (PAR) polymerase 1 (PARP1) activation and PARylation at DNA damage sites, PAR-dependent recruitment of the BAL1 macrodomain-containing protein and its partner E3 ligase, local BBAP-mediated ubiquitylation, and subsequent recruitment of the checkpoint mediators 53BP1 and BRCA1. The PARP1-dependent localization of BAL1-BBAP functionally limits both early and delayed DNA damage and enhances cellular viability independent of ATM, MDC1, and RNF8. These data establish that BAL1 and BBAP are bona fide members of a DNA damage response pathway and are directly associated with PARP1 activation, BRCA1 recruitment, and double-strand break repair.

show abstract

Section: Discussionmentioning

confidence: 99%

BAL1 and Its Partner E3 Ligase, BBAP, Link Poly(ADP-Ribose) Activation, Ubiquitylation, and Double-Strand DNA Repair Independent of ATM, MDC1, and RNF8

Yan

Zhu

et al. 2013

Molecular and Cellular Biology

102

115

View full text Add to dashboard Cite

show abstract

“…PARP is an single-strand DNA breaks (SSBs) repair enzyme. In normal cells, the cells are well resistant against the DNA damage caused by PARP inhibitors, because there is a functional compensation effect from the HR-mediated DNA repair pathway, but the BRCA1/2-deficient cells, which are HR-repair-defective, can't cope with the increasing DNA damage, and then this cells show more hypersensitive to the DNA damage generated by PARP inhibitors (Farmer et al, 2005;McCabe et al, 2006;Balmaña et al, 2011;Basu et al, 2012). It had been proved that the knock down of MCPH1 can impair BRCA1-CHK1 DNA repair pathway and lead to defective HR repair .…”

Section: Discussionmentioning

confidence: 99%

MCPH1 Protein Expression in Normal and Neoplastic Lung Tissues

Zhang

Wu²,

Fan³

et al. 2013

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Lung cancer is the most common cause of cancer-related death in the world. The main types are small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC), the latter including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma. NSCLCs account for about 80% of all lung cancer cases. Microcephalin (MCPH1), also called BRIT1 (BRCT-repeat inhibitor of hTERT expression), plays an important role in the maintenance of genomic stability. Recently, several studies have provided evidence that the expression of MCPH1 gene is decreased in several different types of human cancers. We evaluated the expression of protein MCPH1 in 188 lung cancer and 20 normal lung tissues by immunohistochemistry. Positive MCPH1 staining was found in all normal lung samples and only some cancerous tissues. MCPH1-positive cells were significantly lower in lung carcinoma compared with normal tissues. Furthermore, we firstly found that MCPH1 expression in lung adenocarcinoma is higher than its expression in squamous cell carcinoma. Change in MCPH1 protein expression may be associated with lung tumorigenesis and may be a useful biomarker for identification of pathological types of lung cancer.

show abstract

“…These original observations have led to PARP inhibitors entering subsequent phase II clinical trials in breast and ovarian cancer patients, with or without BRCA mutations [8-10]. At present, the data from clinical studies are not as favorable as promised by the preliminary results [11,12]. Though there might be various causes explaining the clinical performance of the different PARP inhibitors, one of the challenging issues remains on how to identify those patients most receptive to these treatments [13].…”

Section: Introductionmentioning

confidence: 99%

ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition

Montani

Prodosmo²,

Stagni

et al. 2013

J Exp Clin Cancer Res

View full text Add to dashboard Cite

BackgroundMutations in the DNA damage response (DDR) factors, breast cancer 1 (BRCA1) and BRCA2, sensitize tumor cells to poly(ADP-ribose) polymerase (PARP) inhibitors. The ataxia telangiectasia mutated (ATM) kinase is a key DDR protein whose heterozygous germline mutation is a moderate–risk factor for developing breast cancer. In this study, we examined whether ATM inactivation in breast cancer cell lines confers sensitivity to PARP inhibitors.MethodsWild-type BRCA1/2 breast cancer cells (i.e., MCF-7 and ZR-75-1 lines) were genetically manipulated to downregulate ATM expression then assayed for cytostaticity/cytotoxicity upon treatment with PARP inhibitors, olaparib and iniparib.ResultsWhen ATM-depleted cells and their relative controls were treated with olaparib (a competitive PARP-1/2 inhibitor) and iniparib (a molecule originally described as a covalent PARP-1 inhibitor) a different response to the two compounds was observed. ATM-depletion sensitized both MCF-7 and ZR-75-1 cells to olaparib-treatment, as assessed by short and long survival assays and cell cycle profiles. In contrast, iniparib induced only a mild, ATM-dependent cytostatic effect in MCF-7 cells whereas ZR-75-1 cells were sensitive to this drug, independently of ATM inactivation. These latest results might be explained by recent observations indicating that iniparib acts with mechanisms other than PARP inhibition.ConclusionsThese data indicate that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers.

show abstract

Stumbling Blocks on the Path to Personalized Medicine in Breast Cancer: The Case of PARP Inhibitors for BRCA1/2-Associated Cancers

Cited by 42 publications

References 16 publications

BAL1 and Its Partner E3 Ligase, BBAP, Link Poly(ADP-Ribose) Activation, Ubiquitylation, and Double-Strand DNA Repair Independent of ATM, MDC1, and RNF8

BAL1 and Its Partner E3 Ligase, BBAP, Link Poly(ADP-Ribose) Activation, Ubiquitylation, and Double-Strand DNA Repair Independent of ATM, MDC1, and RNF8

MCPH1 Protein Expression in Normal and Neoplastic Lung Tissues

ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition

Contact Info

Product

Resources

About