Deletion of the Importin-alpha Gene in the Breast Cancer Cell

BACKGROUND: BRCA1 (breast-cancer gene 1) is a tumor suppressor gene that accounts for nearly all families of both early onset breast and ovarian cancer and about 45% of families with breast cancer only. Sporadic nonhereditary breast cancer is recognized as the most common form of this malignancy. However, presence of germ-line mutations in the BRCA1 gene of these tumors is an infrequent event. The BRCA1 protein includes a ring domain and an acidic domain, both of which are characteristics of certain transcription factors, as well as two putative nuclear localization signals (NLS) that interact with importin-alpha. The normal BRCA1 protein is located in the nucleus of most breast-cell types whereas the BRCA1 protein of breast cancer cells is aberrantly localized in the cytoplasm. This mislocation of the BRCA1 protein in breast cancer cells may be due to defects in the NLS receptor-mediated pathway for the nuclear import of the BRCA1 gene product. Identification of importin-alpha mutations as a cellular protein responsible for the nuclear import of BRCA1 in breast-cancer cell lines and primary breast cancers is the focus of this investigation. METHODS: A series of 15 surgical samples of breast cancer and 3 samples of breast-cancer cell lines (Hs578T, ZR75-1, MCF-7) was assayed for the presence of the deletion mutant in importin-alpha by using both RT-PCR amplification of importin-alpha transcripts and sequencing analysis. RESULTS: Three of the 15 primary breast cancers and 1 of the 3 breast-cancer cell lines showing deletions in importin-alpha transcripts produced two different truncated transcripts. 1208 bp deletions were observed in transcripts from breast cancer (T-1, T-3) and ZR75-1, which is specified by the nucleotide 251-1458 of the transcript. Another transcript encoded by primary breast cancer (T-2) included a 1312 bp deletion in the nucleotide 61-1372 of the transcript. CONCLUSIONS: The deletions eliminated part of the importin-alpha transcript segment encoding the putative NLS-binding domain but not the importin-beta binding domain, suggesting that these deletion mutants could not bind to NLS of the BRCA1 protein. These results suggest that the composite effects of mislocationof the BRCA1 protein by deletion of the NLS-binding domain in importin-alpha may contribute to tumorigenesis in sporadic breast cancer.

Results of Postoperative Radiation Therapy in 77 Patients of Breast Cancer / 대한암학회지

PURPOSE: This retrospective study was performed to evaluate the effect of postoperative adjuvant radiation therapy of breast cancer on survival, failure patterns and to identify unfavorable prognostic factors. MATERIALS AND METHODS: Seventy-seven patients were analysed retrospectively. Median follow up period was 72 months. According to AJCC system, fifty-eight patients (75%) were advanced than Stage IIb. Among 77 patients, 66 patients (86%) received mastectomy and axillary LN dissection and the other 11 patients (14%) received partial mastectomy and axillary LN dissection. Postoperative radiation therapy with 6 MV X-ray was given to the chest wall and regional lymphatics with total dose of 50 to 55 Gy. Fifty-five patients (71%) received CMF or CAF chemotherapy prior to or after radiation therapy. RESULTS: The 5 year and 10 year survival rate were 64.4% and 51.3%, respectively and 5 year and 10 year disease free survival rate were 57.6% and 47.5%, respectively. Median survival duration was 91 months. Of the 77 patients, 59 patients were evaluable for pattern of failure. Of these, eighteen patients (31%) failed. Initial failure pattern was as follow: 7 (12%) at locoregional, 3 (5%) in distant metastasis, 8 (14%) with locoregional and distant metastasis. But the pattern of final failure at the time of last follow up was contrasted. Distanf failure was the predominant pattern of failure with 29% of patients. Overall survival and disease free survival was significantly influenced by 6 factors with univariated analysis (p<0.05): AJC Stage, T stage, N Stage, number of involved axilliary LN, SCL LN mets, failure pattern. By multivariate analysis the survival difference continued to be significant in 3 factors : T stage, number of involved axillary LN, failure pattern. CONCLUSION: These data demonstrate high locoregional control and survival rate using the combination of surgery and radiotherapy for the patients with locally advanced breast cancer. But predominant failure pattern was distant dissemination. Therefore more effective systemic therapy is needed to improve overall survival.