BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer

Tarón, Miquel; Rosell, Rafael; Felip, Enriqueta; Méndez, Pedro Rafael Casado; Souglakos, John; Ronco, M. Sanchez; Queralt, Cristina; Majó, Joaquim; Sánchez, José Miguel; Sánchez, José Javier; Maestre, José

doi:10.1093/hmg/ddh260

Cited by 281 publications

(223 citation statements)

References 26 publications

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“…In a variety of malignancies including OC, enhanced expression of the DNA repair proteins, Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1), have correlated with resistance to platinum. [2][3][4][5][6] In vitro models have shown that targeting the expression of both BRCA1 and ERCC1 sensitizes cells to platinum-based chemotherapeutic agents, suggesting a potential clinical application to help overcome platinum resistance in OC.…”

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confidence: 99%

“…Although BRCA1 deficiency is generally associated with improved prognosis after platinum-based treatment, not all reports have validated this finding, 12,13 indicating that further studies are needed. Interestingly, low BRCA1 expression has been shown to have prognostic significance in sporadic breast cancer 14 and has correlated with prognosis after platinum-containing chemotherapy in non-small cell lung cancer (NSCLC), 3 suggesting BRCA1 may have a significant role as a biomarker in various tumor types.…”

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confidence: 99%

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The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

Weberpals

Garbuio²,

O'Brien³

et al. 2008

Intl Journal of Cancer

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This study compares Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1) expression as predictive markers and evaluates the in vitro enhancement of platinum sensitivity using targeted agents in sporadic ovarian cancer (OC). A retrospective study was performed of advanced stage OC patients receiving platinum-based chemotherapy. BRCA1 and ERCC1 mRNA expression was determined from frozen tissue of 51 patients. Median overall survival (OS) was longer for patients with lower BRCA1 vs. higher BRCA1 (46 vs.33 months, p 5 0.03). High BRCA1 was predictive of poorer OS specifically in patients with residual disease (RD) <2 cm (p 5 0.03). There was a non-significant association for patients with lower ERCC1 and RD <2 cm in favor of improved OS and time to progression. Patients who expressed higher levels of both BRCA1 and ERCC1 mRNA had a shorter OS compared to patients with lower levels of either or both transcript (33 vs.46 months, p 5 0.04). When Cox proportional modeling was used by representing BRCA1 and ERCC1 mRNA expression as a continuous variable, both emerge as potential predictors of survival. OC cell lines were exposed to chemotherapy in combination with DNA repair pathway inhibitors and cell viability was assessed. In vitro histone deacetylase (HDAC) inhibition increased the sensitivity of A2780s/cp cells to cisplatin and carboplatin but not to taxol, coincident with a significant decrease in BRCA1 and ERCC1 expression, suggesting that this compound directly targets DNA repair. In summary, this study shows that low BRCA1 and ERCC1 expression correlate with improved survival in advanced OC and HDAC inhibition induces synergistic cytotoxicity with platinum in vitro. ' 2008 Wiley-Liss, Inc.Key words: BRCA1; ERCC1; sporadic ovarian cancer; DNA repair; predictive marker Epithelial ovarian cancer (OC) is generally diagnosed at advanced stage resulting in a 5-year survival of only 20-30%. The standard treatment of OC is surgical debulking followed by platinum and taxane chemotherapy. Although 70% of patients with advanced disease initially respond to the first-line regimen, early recurrences and platinum resistance are common obstacles in the management of this disease. Identifying reliable predictors of response and the use of novel therapeutic agents to enhance platinum efficacy are needed to improve the management of OC. Platinum resistance is multifactorial, 1 and an important mechanism of resistance is increased tolerance to platinum-DNA damage and enhanced repair of damaged DNA. In a variety of malignancies including OC, enhanced expression of the DNA repair proteins, Breast Cancer 1 (BRCA1) and excision repair cross complementation group 1 (ERCC1), have correlated with resistance to platinum. [2][3][4][5][6] In vitro models have shown that targeting the expression of both BRCA1 and ERCC1 sensitizes cells to platinum-based chemotherapeutic agents, suggesting a potential clinical application to help overcome platinum resistance in OC.Mutations in the BRCA1 tumor suppressor gene are ...

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The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

Weberpals

Garbuio²,

O'Brien³

et al. 2008

Intl Journal of Cancer

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“…I N addition to substitutions at the protein level, changes in gene regulation are likely to underlie many phenotypes of interest, including adaptations and human diseases (Britten and Davidson 1971;King and Wilson 1975;Jin et al 2001;Carroll 2003;Abzhanov et al 2004;Iftikhar et al 2004;Shapiro et al 2004;Taron et al 2004). Regulation of gene expression may be achieved by a large number of transcriptional and translational mechanisms (reviewed in Wray et al 2003).…”

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Using Reporter Gene Assays to IdentifycisRegulatory Differences Between Humans and Chimpanzees

et al. 2007

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Most phenotypic differences between human and chimpanzee are likely to result from differences in gene regulation, rather than changes to protein-coding regions. To date, however, only a handful of human-chimpanzee nucleotide differences leading to changes in gene regulation have been identified. To hone in on differences in regulatory elements between human and chimpanzee, we focused on 10 genes that were previously found to be differentially expressed between the two species. We then designed reporter gene assays for the putative human and chimpanzee promoters of the 10 genes. Of seven promoters that we found to be active in human liver cell lines, human and chimpanzee promoters had significantly different activity in four cases, three of which recapitulated the gene expression difference seen in the microarray experiment. For these three genes, we were therefore able to demonstrate that a change in cis influences expression differences between humans and chimpanzees. Moreover, using sitedirected mutagenesis on one construct, the promoter for the DDA3 gene, we were able to identify three nucleotides that together lead to a cis regulatory difference between the species. High-throughput application of this approach can provide a map of regulatory element differences between humans and our close evolutionary relatives.

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“…However, the relatively narrow range of ERCC1 expression in the mid-range of the maximal expression spectrum suggests that MBC is only moderately platinum sensitive, and that ERCC1 expression levels may not be useful for therapeutic decisions on platinum use for MBC [23]. In contrast, BRCA1 expression levels had a wide range in MBC, which may provide an opportunity for its use as a predictive marker for platinum efficacy [24]. However, in contrast to RRM1 and ERCC1 where activating or inactivating mutations have not been described, assessment of the mutational status of BRCA1 may be crucial to the interpretation of the prognostic and predictive utility of its protein levels [25][26][27].…”

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confidence: 99%

In Situ Protein Expression of RRM1, ERCC1, and BRCA1 in Metastatic Breast Cancer Patients Treated with Gemcitabine-Based Chemotherapy

Metro¹,

Zheng²,

Fabi³

et al. 2009

LCNV

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Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small cell lung cancer and pancreatic cancer. We investigated the protein levels of RRM1 and two other DNA repair enzymes, ERCC1 and BRCA1, in 55 metastatic breast cancer (MBC) patients undergoing gemcitabine-based chemotherapy. With automated in situ protein quantification (AQUA v1.6), the average scores for RRM1, ERCC1 and BRCA1 ranged from 245.6-2,774.1, 74.0-410.3 and 54.4-1,833.1, respectively. They were significantly associated with each other (Spearman's rho ≥ .36; P ≤ 0.007). Given their pattern of distribution, RRM1 and BRCA1 are potentially suitable markers for clinical decision making in MBC.

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BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer

Cited by 281 publications

References 26 publications

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer

Using Reporter Gene Assays to IdentifycisRegulatory Differences Between Humans and Chimpanzees

In Situ Protein Expression of RRM1, ERCC1, and BRCA1 in Metastatic Breast Cancer Patients Treated with Gemcitabine-Based Chemotherapy

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