This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yoshikawa, K. Articles by Takahashi, R. Search for Related Content PubMed PubMed Citation Articles by Yoshikawa, K. Articles by Takahashi, R.

Reduction of BRCA1 Protein Expression in Japanese Sporadic Breast Carcinomas and Its Frequent Loss in BRCA1-associated Cases

Departments of Pathology and Tumor Biology [K. Y., H. S., K. S., T. O., T. S., R. T.] and Gastroenterological Surgery [K. Y., H. S., A. Y., Y. Y.], and Division of Science of Nursing [T. I.], Kyoto University Graduate School of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan; First Department of Surgery, Ehime University School of Medicine, Onsen-gun, Ehime 791-02, Japan [K. H.]; Kodama Breast Clinic, Kitanokamihakubai-cho, Kita-ku, Kyoto 606, Japan [H. K.]; Department of Surgical Oncology, Osaka University Graduate School of Medicine, Yamadagaoka, Suita, Osaka 565, Japan [S. N.]; and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75235 [A. F. G.]

BRCA1 is a tumor suppressor gene that is responsible for hereditary breast and ovarian cancer syndrome. To clarify the possible involvement of the BRCA1 protein in mammary carcinogenesis in sporadic and hereditary forms, we have analyzed the BRCA1 protein expression pattern in five breast epithelial cell lines, including a BRCA1-deficient cell line, and 162 breast cancer tissue samples [including 108 sporadic, 35 hereditary (BRCA1 status unknown), and 19 BRCA1-associated cases] from Japanese women. Twelve anti-BRCA1 antibodies were tested by fixation conditions, in which nuclear localization of BRCA1 protein was preserved, and by specificity of the antibodies, which was evaluated in BRCA1-deficient cancer cells. Using monoclonal antibodies applicable to immunohistochemical analysis of paraffin-embedded tissue sections, we found high-level expression of BRCA1 protein in normal mammary epithelium and various degrees of reduced expression in breast cancer cells. Of the 19 BRCA1-associated breast cancer tissues, 15 (79%) showed reduction (8 cases) or complete loss (7 cases) of nuclear expression. Thirty (28%) of 108 sporadic and 6 (17%) of 35 hereditary carcinomas showed reduced BRCA1 protein expression. Reduction of BRCA1 protein expression in sporadic carcinomas was associated with solid-tubular phenotype, with poor tubular differentiation, and with an overexpression of c-erbB-2 protein, which is one of the prognostic factors in breast cancer. Our data suggest that reduced expression of BRCA1 protein may play an important role in mammary carcinogenesis, not only in BRCA1-associated breast carcinomas, but also in sporadic carcinomas, and also suggest that mechanisms other than mutation may be involved in its reduced expression.

This article has been cited by other articles:

				A. D. Spearman, K. Sweet, X.-P. Zhou, J. McLennan, F. J. Couch, and A. E. Toland Clinically Applicable Models to Characterize BRCA1 and BRCA2 Variants of Uncertain Significance J. Clin. Oncol., November 20, 2008; 26(33): 5393 - 5400. [Abstract] [Full Text] [PDF]

				J. I. Weberpals, K. V. Clark-Knowles, and B. C. Vanderhyden Sporadic Epithelial Ovarian Cancer: Clinical Relevance of BRCA1 Inhibition in the DNA Damage and Repair Pathway J. Clin. Oncol., July 1, 2008; 26(19): 3259 - 3267. [Abstract] [Full Text] [PDF]

				F. Al-Mulla, M. Abdulrahman, G. Varadharaj, N. Akhter, and J. T. Anim BRCA1 Gene Expression in Breast Cancer: A Correlative Study between Real-time RT-PCR and Immunohistochemistry J. Histochem. Cytochem., May 1, 2005; 53(5): 621 - 629. [Abstract] [Full Text] [PDF]

				S. Staff, J. Isola, and M. Tanner Haplo-insufficiency of BRCA1 in Sporadic Breast Cancer Cancer Res., August 15, 2003; 63(16): 4978 - 4983. [Abstract] [Full Text] [PDF]

				T I Orban and E Olah Emerging roles of BRCA1 alternative splicing Mol. Pathol., August 1, 2003; 56(4): 191 - 197. [Abstract] [Full Text] [PDF]

				G. Baldassarre, S. Battista, B. Belletti, S. Thakur, F. Pentimalli, F. Trapasso, M. Fedele, G. Pierantoni, C. M. Croce, and A. Fusco Negative Regulation of BRCA1 Gene Expression by HMGA1 Proteins Accounts for the Reduced BRCA1 Protein Levels in Sporadic Breast Carcinoma Mol. Cell. Biol., April 1, 2003; 23(7): 2225 - 2238. [Abstract] [Full Text] [PDF]

				W. Reed, B. Sandstad, R. Holm, and J. M. Nesland The Prognostic Impact of Hormone Receptors and c-erbB-2 in Pregnancy-Associated Breast Cancer and Their Correlation with BRCAI and Cell Cycle Modulators International Journal of Surgical Pathology, April 1, 2003; 11(2): 65 - 74. [Abstract] [PDF]

				K. Miyamoto, T. Fukutomi, K. Asada, K. Wakazono, H. Tsuda, T. Asahara, T. Sugimura, and T. Ushijima Promoter Hypermethylation and Post-transcriptional Mechanisms for Reduced BRCA1 Immunoreactivity in Sporadic Human Breast Cancers Jpn. J. Clin. Oncol., March 1, 2002; 32(3): 79 - 84. [Abstract] [Full Text] [PDF]

				Y. Matsutani, A. Yamauchi, R. Takahashi, M. Ueno, K. Yoshikawa, K. Honda, H. Nakamura, H. Kato, H. Kodama, T. Inamoto, et al. Inverse Correlation of Thioredoxin Expression with Estrogen Receptor- and p53-dependent Tumor Growth in Breast Cancer Tissues Clin. Cancer Res., November 1, 2001; 7(11): 3430 - 3436. [Abstract] [Full Text] [PDF]

				A Perez-Valles, M Martorell-Cebollada, E Nogueira-Vazquez, J A Garcia-Garcia, and E Fuster-Diana The usefulness of antibodies to the BRCA1 protein in detecting the mutated BRCA1 gene. An immunohistochemical study J. Clin. Pathol., June 1, 2001; 54(6): 476 - 480. [Abstract] [Full Text] [PDF]

				C. Beger, L. N. Pierce, M. Kruger, E. G. Marcusson, J. M. Robbins, P. Welcsh, P. J. Welch, K. Welte, M.-C. King, J. R. Barber, et al. Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach PNAS, January 2, 2001; 98(1): 130 - 135. [Abstract] [Full Text] [PDF]

				J. C. Rice and B. W. Futscher Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter Nucleic Acids Res., September 1, 2000; 28(17): 3233 - 3239. [Abstract] [Full Text] [PDF]

				J. C. Rice, H. Ozcelik, P. Maxeiner, I. Andrulis, and B. W. Futscher Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens Carcinogenesis, September 1, 2000; 21(9): 1761 - 1765. [Abstract] [Full Text] [PDF]