BRCA1 Levels Research Articles

Antisense Inhibition of BRCA1 Expression and Molecular Analysis of Hereditary Tumors Indicate That Functional Inactivation of the p53 DNA Damage Response Pathway Is Required for BRCA-Associated Tumorigenesis

Objective. The purpose of this investigation was to test the hypothesis that mutation of TP53 is a requirement for BRCA-associated cancer development.Methods. A cell line experimentally deficient in BRCA1 protein was constructed using a regulatable antisense expression vector expressing 4000 bp from the BRCA1 cDNA. Changes in BRCA1, p53, and p21 protein levels were assayed by immunoblotting. Ovarian tumors with germline mutations in BRCA1 or BRCA2 were screened for mutations in TP53 by single-strand conformation polymorphism analysis.Results. Antisense inhibition of BRCA1 protein caused p53 and p21 protein levels to rise, indicating that partial loss of BRCA1 function activates the p53 DNA damage response pathway. Somatic mutation of TP53 was observed in 7 of 14 BRCA-associated ovarian tumors.Conclusions. Our findings provide novel evidence that loss of BRCA1 function in human cells activates the p53 DNA damage response pathway and that loss of this pathway, by somatic mutation of TP53, is a likely requirement for BRCA-associated tumor development.

Quantitative Analysis of BRCA1 and BRCA2 mRNA Expression in Sporadic Breast Carcinomas and Its Relationship with Clinicopathological Characteristics

BRCA1 and BRCA2 mRNA expression in sporadic breast cancers was quantified by a real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR), and the relationship of their expression with various Clinicopathological factors was studied. BRCA2 mRNA levels (0.993±1.395, mean±SD (BRCA2/β‐glucuronidase mRNA ratios)) were significantly (P<0.01) higher than BRCA1 mRNA levels (0.519±0.570 (BRCAl/p‐glucuronidase mRNA ratios)), and a weak but significant (r=0.390, P<0.01) correlation was observed between BRCA1 and BRCA2 mRNA expression levels. There was no significant association between BRCA1 mRNA expression and Clinicopathological factors such as menstrual status, tumor size, lymph node status, estrogen and progesterone receptor status, and histological grade. On the other hand, there was a significant association between higher BRCA2 mRNA expression and estrogen receptor (ER) negativity (P<0.01) or progesterone receptor (PR) negativity (P<0.01) or high histological grade (P<0.01). These results suggest a differential contribution of BRCA1 and BRCA2 in the pathogenesis of sporadic breast cancers. BRCA2 mRNA is speculated to be up‐regulated in response to proliferation and genomic instability in high histological grade tumors.

Expression of Brca1 and splice variant Brca1delta11 RNA levels in mouse mammary gland during normal development and tumorigenesis.

Expression of Brca1 in mouse mammary cancer has yet to be analysed. We use a progressive model of neoplasia based on several mouse epithelial cell lines that represent distinct steps toward the fully tumorigenic state. Using RNase protection analysis because acceptable anti-Brca1 antibodies are not available we investigated the expression of Brca1 and a splice variant, Brca1Delta11, in several mammary hyperplasias and tumors that arose from them, and in normal mammary gland through pregnancy and involution. Expression of Brca1 was highest in rapidly proliferating cells. Expression of the full-length Brca1 was detectable in the virgin gland, was slightly elevated in the midpregnant gland, and decreased to levels similar to the age-matched virgin gland in the completely involuted gland. Expression of both forms of Brca1 was detectable in 9/9 paired hyperplasias and tumors, with levels of total Brca1, but not the splice variant Brca1Delta11, in tumors higher than those in the hyperplasias. While in disagreement with the observation that Brca1 levels decrease in human breast cancer progression, these patterns support the notion that Brca1 expression is associated with proliferating cells, and suggests that the link with differentiation seen in normal cells can be removed when cells become tumorigenic.

Tumor suppressor p53 is required to modulate BRCA1 expression.

Individuals carrying mutations in BRCA1 or p53 genes are predisposed to a variety of cancers, and both tumor suppressor genes have been implicated in DNA damage response pathways. We have analyzed a possible functional link between p53 and BRCA1 genes. Here we show that BRCA1 expression levels are down-regulated in response to p53 induction in cells that undergo either growth arrest, senescence, or apoptosis. Physiological stimuli, such as exposure to DNA-damaging agents, also result in negative regulation of BRCA1 levels in a p53-dependent manner prior to causing cell cycle arrest. Nuclear run-on experiments and luciferase reporter assays demonstrate that the changes in BRCA1 expression are mainly due to transcriptional repression induced by p53. In conclusion, the data show that BRCA1 expression levels are controlled by the presence and activity of wild-type p53 and suggest the existence of an intracellular p53/BRCA1 pathway in the response of cells to stress conditions.

Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens.

Functional inactivation of BRCA1 is an important mechanism involved in breast cancer pathogenesis. Mutation is often responsible for BRCA1 inactivation in familial breast cancer, but is not responsible for the decreased levels of BRCA1 seen in a subset of sporadic breast cancer patients. To determine if aberrant cytosine methylation of the BRCA1 promoter is associated with decreased BRCA1 gene expression in human breast cancer, high resolution bisulfite sequence analysis was used to analyze the cytosine methylation status of the BRCA1 promoter in 21 axillary node negative breast cancer patients with known levels of BRCA1 expression. Aberrant cytosine methylation of the BRCA1 promoter was detected in three of 21 patient specimens. These three specimens also expressed the lowest levels of BRCA1. Results from this analysis show that aberrant cytosine methylation of the BRCA1 promoter is directly correlated with decreased levels of BRCA1 expression in human breast cancer, and suggest that epigenetic silencing may be one mechanism of transcriptional inactivation of BRCA1 in sporadic mammary carcinogenesis.

Disruption of Cell Cycle Kinetics by Benzo[a]pyrene: Inverse Expression Patterns of BRCA-1 and p53 in MCF-7 Cells Arrested in S and G2

The effects of a ligand of the aromatic hydrocarbon receptor (AhR), benzo[a]pyrene(B[a]P), and its metabolite, BPDE (7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene), on BRCA-1 levels and cell cycle kinetics were determined in MCF-7 breast cancer cells. Exposure of asynchronous MCF-7 cells for 72 hours to a non-cytotoxic dose of 0.5 μM B[a]P triggered a three-fold reduction in BRCA-1 protein. In MCF-7 cells resistant. (20% to 30%) to genotoxic concentrations of B[a]P (1 to 5 μM), the loss of BRCA-1 protein was coupled with pausing in S-phase and G2/M, and accumulation of p53, mdm2 and p21. Treatment of MCF-7 cells synchronized in S-phase (72%) with B[a]P prolonged the arrest in S-phase, although this checkpoint was transient since cells resumed to G2/M after 12 hours with reduced levels of BRCA-1. In these cells, levels of p53 were increased, whereas the cellular content of p21 remained unaltered. In contrast, the co-treatment with the AhR antagonist, α-naphthoflavone (ANF), abrogated the deleterious effects of B[a]P on BRCA-1 expression, while preventing the accumulation of p53 and disruption of cell cycle profile. These findings suggest that the AhR mediated the inverse expression patterns of BRCA-1 and p53 upon exposure to B[a]P. The treatment with BPDE induced S-phase arrest and reduced BRCA-1 mRNA levels. The negative effects of BPDE on BRCA-1 expression were not transient since removal of BPDE did not allow complete reversal of the repression. These cumulative data suggest that the B[a]P metabolite, BPDE, may play a key role in disruption of BRCA-1 expression and cell cycle kinetics in breast epithelial cells.

Kinetics of BRCA1 regulation in response to UVC radiation.

To investigate changes in BRCA1 following DNA damage, we exposed MCF-7 cells to increasing doses of ultraviolet C. We observed an increase in BRCA1 protein levels above 78 J/m2. This increase was observed as early as 5 min after irradiation. BRCA1 levels were then observed to decrease after 2 h, consistent with the previously published data. By pretreating with cycloheximide prior to irradiation, we observed a decrease in the protein half-life, from 3.5 h to 53 min, suggesting that a decrease in protein half-life may cause the lower levels of BRCA1 after irradiation. We also observed an increase in BRCA1 mRNA within 15 min of irradiation, followed by a decrease after 4 h. These data suggest that newly translated protein may contribute to increases in BRCA1 protein levels. The very rapid changes in BRCA1 support its role as a sensor of DNA damage, as opposed to being a repair gene.

Altered expression of BRCA1, BRCA2, and a newly identified BRCA2 exon 12 deletion variant in malignant human ovarian, prostate, and breast cancer cell lines.

Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast, ovarian, and possibly prostate cancer, yet structural mutations in these genes are infrequent in sporadic cancer cases. To better define the involvement of these genes in sporadic cancers, we characterized expression levels of BRCA1 and BRCA2 transcripts in cancer cell lines derived from neoplasms of the ovary, prostate, and breast and compared them with those expressed in primary cultures of normal epithelial cells established from these organs. We observed upregulation of BRCA1 and/or BRCA2 expression in six of seven ovarian cancer cell lines (OVCA420, OVCA429, OVCA432, ALST, DOV13, and SKOV3) when compared with levels found in normal ovary surface epithelial cells. Furthermore, five cancerous or immortalized prostatic epithelial cell lines (BPH-1, TSU-Pr1, LNCaP, PC-3, and DU145) also expressed higher levels of BRCA1 and/or BRCA2 mRNA than did primary cultures of normal prostatic epithelial cells. In contrast, only the estrogen receptor-positive MCF-7 cell line overexpressed these messages, whereas the estrogen receptor-negative breast cancer cell lines Hs578T, MDA-MB-231, and MDA-MB-468 showed no change in expression levels when compared with normal breast epithelial cells. In addition, expanding on our recent identification of a novel BRCA2 transcript variant carrying an in-frame exon 12 deletion (BRCA2 delta 12), we report increased expression of this variant in several ovarian, prostate, and mammary cancer cell lines (OVCA420, OVCA433, ALST, DOV13, SKOV3, TSU-Pr1, DU145, and MDA-MB-468). Most notably, high levels of BRCA2 delta 12 mRNA were detected in an estrogen receptor-positive breast cancer cell line, MCF-7, and in an androgen-independent prostate cancer cell line, DU-145. Interestingly, the wild-type BRCA2 transcript was barely detectable in DU145, which could be used as a model system for future investigations on BRCA2 delta 12 function. Taken together, our data suggest disruption of BRCA1 and/or BRCA2 gene expression in certain epithelial cancer cell lines of the ovary, prostate, and breast. Because wild-type BRCA1 and BRCA2 gene products increase during cell-cycle progression and are believed to exert growth-inhibitory action, enhanced expression of these genes in cancer cells may represent a negative feedback mechanism for curbing proliferation in fast-growing cells. At present, the functionality of BRCA2 delta 12 remains elusive.

The Brn-3b POU family transcription factor represses expression of the BRCA-1 anti-oncogene in breast cancer cells.

The BRCA-1 tumour supressor gene was identified on the basis of mutations which occur in familial breast cancer indicating that its inactivation can cause this disease. Although BRCA-1 does not appear to be mutated in sporadic breast cancer, its expression has been shown to be reduced in tumour material from such cases. We show here that mammary tumours which have reduced levels of BRCA-1 expression show enhanced expression of the Brn-3b POU family transcription factor at both the mRNA and protein levels. This elevated expression of Brn-3b is not found in normal mammary cells, benign tumours or in malignant tumour samples which do not exhibit reduced levels of BRCA-1. In contrast, no correlation was noted between BRCA-1 and expression of the related factor Brn-3a. Moreover, Brn-3b but not Brn-3a can strongly repress the BRCA-1 promoter approximately 20-fold in mammary tumour cells. To our knowledge, this is the first report of a transcription factor which regulates BRCA-1 expression. Thus, Brn-3b may play an important role in regulating expression of BRCA-1 in mammary tumours with enhanced expression of Brn-3b resulting in reduced BRCA-1 expression and thereby being potentially important in tumour development.

An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers.

The presence of BRCA1 protein was determined immunohistochemically in normal and benign breast biopsies, non-familial breast carcinomas and breast carcinomas from one or more individuals from 8 BRCA1 families. Strikingly, little staining was detected in breast carcinomas from BRCA1 families, regardless of the position or type of mutation, whereas strong immunostaining was observed in 28/28 of non-malignant breast biopsies. Furthermore, BRCA1 staining was reduced in non-familial breast carcinomas, since loss of nuclear BRCA1 staining was evident in 19% of non-familial breast carcinomas whilst a similar proportion (20%) showed absence of either cytoplasmic or nuclear BRCA1 staining. Statistical analysis indicates that breast cancer is characterised by a reduction in levels of nuclear BRCA1 in familial (p < 0.001) and non-familial breast cancer (p = 0.001). In non-familial breast cancer absence of nuclear BRCA1, but not cytoplasmic BRCA1, is more common in high grade breast carcinomas (p = 0.03) and in patients with evidence of lymph node involvement (p = 0.05). Correlation between the absence of BRCA1 protein with high grade is consistent with previous findings of a correlation between mutations in the BRCA1 gene and high grade. Our findings provide new evidence in support of BRCA1 as a tumour suppressor protein in non-familial breast cancer.

Down-regulation of BRCA1 and BRCA2 in human ovarian cancer cells exposed to adriamycin and ultraviolet radiation.

Germ-line mutations of the BRCA1 and BRCA2 genes predispose women to develop cancers of the breast and ovary, but the biologic functions of these genes remains unclear. We have investigated the responses of the BRCA1 and BRCA2 gene products to cytotoxic agents in 3 human ovarian cancer cell lines: SK-OV-3 (which contains a p53 deletion mutation), CAOV-3 (which over-expresses a mutant p53) and PA-1 (which expresses wild-type p53). In screening studies, we determined the effects of 7 different agents on BRCA1 and BRCA2 expression. We found that Adriamycin (ADR) and ultraviolet (UV)radiation significantly down-regulated BRCA1 and BRCA2 mRNA expression in SK-OV-3 cells. On the other hand, camptothecin, nitrogen mustard, taxol, vincristine and etoposide had no effect on BRCA1 or BRCA2 mRNA levels at doses that yielded degrees of cytotoxicity similar to or greater than ADR. The down-regulation of BRCA1 and BRCA2 mRNAs was dose and time dependent; significant down-regulation was first observed at 8-16 hr after exposure to ADR. BRCA1 protein levels were also down-regulated following treatment of SK-OV-3 cells with ADR. Similar results were observed in CAOV-3 and PA-1 cells treated with ADR, and this finding could not be directly attributed to ADR-induced changes in the cell cycle distribution. The ADR doses required for significant decreases of BRCA1 and BRCA2 were about 10-15, 5-10 and 2 microM, respectively, for SK-OV-3, CAOV-3 and PA-1; the IC50 doses for loss of cell viability (determined by Trypan blue dye exclusion) were 23, 14 and 0.4 microM, respectively. Thus, at equitoxic doses of ADR, PA-1 cells were more resistant to down-regulation of BRCA1 and BRCA2 than SK-OV-3 or CAOV-3. Our findings suggest that 1) BRCA1 and BRCA2 expression in human ovarian cancer cell lines is selectively down-regulated by 2 DNA-damaging agents (ADR and UV radiation); 2) these responses are not due to non-specific cytotoxicity; and 3) the BRCA1 and BRCA2 responses may be dependent, in part, on the p53 functional status of the cells. We speculate that the down-regulation of BRCA1 and BRCA2 may be part of a cellular survival response activated by certain forms of DNA damage.

Preferential allelic expression can lead to reduced expression of BRCA1 in sporadic breast cancers

BRCA1 is considered to be a tumor-suppressor gene, yet mutations in this gene are uncommon in sporadic breast tumors. We investigated whether mechanisms other than DNA mutations that affect the coding region might be involved in breast carcinogenesis. Since loss of expression of the BRCA1 gene would lead to lack of protein, we evaluated the level of BRCA1 mRNA in 21 normal epithelial specimens and in 74 breast carcinomas using quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR). All normal breast epithelial samples expressed BRCA1 mRNA. On the other hand, the tumor specimens exhibited approximately 10-fold range of levels of BRCA1, with some specimens expressing barely detectable amounts of BRCA1 mRNA. The distribution in levels was significantly higher in normal breast epithelial cells than in tumor specimens (p = 0.004). Examination of the BRCA1 locus indicated that deletion of the BRCA1 gene may account for low levels of BRCA1 in a number of specimens. In addition, analysis of samples with relatively reduced levels of BRCA1 expression revealed preferential allele-specific expression in a number of cases, suggesting the presence of regulatory mutations. Our data suggest that the BRCA1 gene may be involved in sporadic breast carcinogenesis through a reduction in gene expression. Int. J. Cancer 77:1–6, 1998.© 1998 Wiley-Liss, Inc.

Preferential allelic expression can lead to reduced expression of BRCA1 in sporadic breast cancers.

BRCA1 is considered to be a tumor-suppressor gene, yet mutations in this gene are uncommon in sporadic breast tumors. We investigated whether mechanisms other than DNA mutations that affect the coding region might be involved in breast carcinogenesis. Since loss of expression of the BRCA1 gene would lead to lack of protein, we evaluated the level of BRCA1 mRNA in 21 normal epithelial specimens and in 74 breast carcinomas using quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR). All normal breast epithelial samples expressed BRCA1 mRNA. On the other hand, the tumor specimens exhibited approximately 10-fold range of levels of BRCA1, with some specimens expressing barely detectable amounts of BRCA1 mRNA. The distribution in levels was significantly higher in normal breast epithelial cells than in tumor specimens (p = 0.004). Examination of the BRCA1 locus indicated that deletion of the BRCA1 gene may account for low levels of BRCA1 in a number of specimens. In addition, analysis of samples with relatively reduced levels of BRCA1 expression revealed preferential allele-specific expression in a number of cases, suggesting the presence of regulatory mutations. Our data suggest that the BRCA1 gene may be involved in sporadic breast carcinogenesis through a reduction in gene expression.

Regulation of BRCA1 and BRCA2 expression in human breast cancer cells by DNA-damaging agents

Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to the development of breast cancer, ovarian cancer, and other malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may function in the sensing and/or repair of DNA damage. To investigate this possibility, we determined the effects of various DNA-damaging agents and other cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other human breast cancer cell lines. We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin (a topoisomerase I inhibitor), and ultraviolet radiation induced significant decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 mRNAs were observed within 6-12 h after treatment with adriamycin and persisted for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; but these decreases required several days. U.V. radiation induced dose-dependent down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed at doses that yielded relatively little cytotoxicity and little or no apoptotic DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and time-dependent alterations in the cell cycle distribution; but these alterations did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels was correlated with p53 functional status. MCF-7 cells transfected with a dominant negative mutant p53 (143 val-->ala) required at least tenfold higher doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental MCF-7 cells or control-transfected MCF-7 clones. These results suggest that BRCA1 and BRCA2 may play roles in the cellular response to DNA-damaging agents and that there may be a p53-sensitive component to the regulation of BRCA1 and BRCA2 mRNA expression.

Molecular characterization of intraductal breast carcinomas.

In situ duct carcinoma (DCIS) is a heterogeneous group of lesions which has recently been subdivided into three types: well-differentiated (type I), intermediately differentiated (type II) and poorly differentiated (type III) DCIS. Fourteen cases of DCIS and 11 of DCIS with minimal invasion were analysed for mRNA levels of beta-actin, EGFR, c-cerbB2, MTS1, k-ras, RB, BRCA1, cyclin E, and c-myc genes. A microdissection technique was used on paraffin-embedded tissue. A statistically significantly higher expression of cyclin E oncogene and MTS1 tumor suppressor gene was seen in type III DCIS than in the other types, while no significant differences in the mRNA expression patterns of the other genes were observed. These data are consistent with the fact that poorly differentiated DCIS is a readily recognizable class of tumours that have a particularly aggressive behaviour and probably unique histogenesis.

Breast cancer genes: therapeutic strategies.

Although effective treatments for breast cancer predated the identification of causative molecular defects in humans, it is widely hoped that an understanding and/or manipulation of the key genetic events will lead to even more effective therapies or even cures. Powerful methods of positional cloning and gene identification have identified the breast cancer genes, BRCA1 and BRCA2, which together are responsible for the majority of cases of hereditary breast and ovarian cancer. Although the BRCA1 gene is rarely mutated in sporadic breast or ovarian cancer, levels of BRCA1 mRNA and protein are markedly decreased in the majority of sporadic cases of cancer. This suggests that hereditary and sporadic breast cancer share common genetic themes and that treatments aimed at increasing levels of BRCA1 or BRCA2 may be useful for both hereditary and sporadic cancers. We have demonstrated that gene transfer of wild-type BRCA1 inhibits the growth of sporadic breast and ovarian cancer cells and suppresses growth of established breast and ovarian tumor models in nude mice. Mutant BRCA1 genes do not inhibit growth or suppress tumor, providing additional evidence that BRCA1 is a tumor-suppressor gene. Strategies designed to increase BRCA1 expression or development of BRCA1-mimetic agents may be ultimately useful as therapeutic approaches.

The progestin ORG2058 but not retinoic acid stimulates BRCA1 mRNA expression in MCF-7 human breast cancer cells

BRCA1 has been characterized as one of the major breast cancer susceptibility genes. Although no BRCA1 mutations have been reported in sporadic breast cancer, altered levels of BRCA1 are found in non hereditary breast malignant lesions. Therefore, BRCA1 is potentially playing a key role in the genesis of breast cancer. In this study, we explored the effects of estradiol and two differentiating agents, the progestin ORG2058 and retinoic acid, on BRCA1 mRNA expression in human estrogen and progesterone receptor positive MCF-7 cells. Using RNAse protection assay, we have demonstrated that ORG2058 induces a major (50 times) stimulation of BRCA1 mRNA expression. The maximum induction effect was obtained at the pharmacological dose of 100 nM and after 48 h of treatment. While estradiol generated an expected increase of BRCA1 mRNA, retinoic acid did not produce any effects. Our results demonstrate for the first time that BRCA1 is specifically up-regulated by a progestin, a steroid known to induce the differentiation of epithelial mammary cells. The absence of retinoic acid effect suggests that a specific progesterone-dependent pathway, could control BRCA1 expression.

ERCC1 and BRCA1 mRNA expression predicts the clinical outcome of non-small cell lung cancer receiving platinum-based chemotherapy.

Objective: We conducted a perspective study to investigate the association between mRNA expression quantities of ERCC1, BRCA1, RRM1 and RRM2 and response to chemotherapy and clinical outcome of advance Non-Small Cell Lung Cancer.(NSCLC). Methods: Two hundred eight patients who were diagnosed as advanced stage NSCLC were included in our study. A fluorescence-based and real-time detection method was used to determine the relative cDNA quantification for ERCC1, BRCA1, RRM1 and RRM2, and β-actin was used as the reference gene. Results: The median expression levels of ERCC1, BRCA1, RRM1 and RRM2 mRNA were 0.67±0.17, 0.095±0.012, 0.24±0.17 and 2.45±0.32, respectively. Our study found that the low ERCC1 (OR=1.82, 95% CI=1.01-3.20) and Low BRCA1 (OR=2.53, 95%CI=1.38-4.64) mRNA expression was more likely to response to chemotherapy when compared with high expression, respectively. Multivariate Cox regression analysis indicated that patients with low mRNA expression of ERCC1 and BRCA1 attained 0.43 (OR=0.43, 95%CI=0.27-0.89) and 0.37 (OR=0.37, 95%CI=0.22-0.66) fold risk of death from NSCLC. However, we found RMM1 and RRM2 mRNA expression could not influence the response to chemotherapy and clinical outcome of NSCLC. Conclusion: ERCC1 and BRCA1 mRNA expression could be important predictive markers for individualized platinum-based chemotherapy for NSCLC patients.