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

Abstract

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 β β β-glucuronidase mRNA ratios)) were significantly (P < < < <0.01) higher than BRCA1 mRNA levels (0.519 ± ± ± ±0.570 (BRCA1/ β β β β-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. Key words: Breast cancer -BRCA1 -BRCA2 -mRNA expression -RT-PCRBRCA1 and BRCA2 are well-established breast cancer susceptibility genes, which were cloned through linkage analysis using large breast cancer families.1, 2) Germline mutations of these two genes account for 40-50% of sitespecific breast cancer families, 3,4) and life-time risk of breast cancers among BRCA1 or BRCA2 germline mutation carriers is reported to be 56%-85%.5-7) Both behave as classical tumor suppressor genes, loss of both alleles being required for carcinogenesis. Although the functions of BRCA1 and BRCA2 are far from clear, recent studies have revealed that BRCA1 and BRCA2 form a complex with Rad51 and are involved in the repair of double-strand DNA breaks as well as mitotic and meiotic recombination. In addition, BRCA1 was shown to inhibit cell growth when it was transfected to breast cancer cells in vitro and in vivo. 8)Somatic mutations of BRCA1 and BRCA2 seem to be a very rare event, 9-12) but loss of heterozygosity (LOH) is frequently observed at 17q12-q21 and 13q12-q13, suggesting implication of these two genes in the pathogenesis of breast cancers through not a structural, but a regulatory mutation or through hypermethylation of a promoter region, leading to attenuated transcription. It has been shown that BRCA1 mRNA levels are down-regulated in sporadic breast cancers as compared with the normal breast tissues, and hypermethylation of the promoter region of BRCA1 explains this down-regulation in some sporadic breast cancers. 13,14) On the other hand, BRCA2 mRNA levels do not show a consistent tendency, and may be either up-regulated or down-regulated among sporadic breast cancers. 15)Unlike BRCA1, the promoter region of BRCA2 has been sho...

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

“…Consistent with our previous report, 20 we have shown, in the present study, that upregulation of BRCA2 mRNA is associated with an aggressive phenotype of breast tumors, i.e., high histologic grade and ER negativity. In addition, we have previously shown that high BRCA2 mRNA levels are associated with high mitotic activity and nuclear pleomorphism.…”

“…In addition, we have previously shown that high BRCA2 mRNA levels are associated with high mitotic activity and nuclear pleomorphism. 20 These results are consistent with a model in which BRCA2 exerts a positive effect on proliferation. Such a model, however, is very unlikely to reconcile with the fact that BRCA2 is a tumor-suppressor gene that should inhibit proliferation.…”

“…These patients were different from those analyzed in our previous reports. 20,21 Patient characteristics are shown in Table I. Patients had a physical examination every 3 months for 2 years postoperatively and every 6 months thereafter.…”

“…20 In brief, the sequence of a probe for BRCA2 was 5Ј-TGATCCCAAGTGGTCCAC-CCCAAC-3Ј. The probe was labeled by 6-carboxyfluorescein (FAM) fluorescent spectrum as a reporter.…”

“…We have also studied the relationship between BRCA2 mRNA levels determined by real-time PCR and clinicopathologic characteristics of sporadic breast cancers and have obtained results consistent with those of Bieche et al, 15 i.e., that high BRCA2 mRNA levels are significantly associated with high histologic grade and estrogen receptor (ER) negativity. 20 These observations suggest that high BRCA2 mRNA expression might be associated with poor prognosis. Therefore, in the present study, we studied the significance of BRCA2 mRNA expression as a prognostic factor in sporadic breast cancers.…”