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• W2024581019 abstract "Two genes, BRCA1 (Miki et al., 1994) and BRCA2 (Wooster et al., 1995), have been implicated in inherited predisposition to female breast cancer. Mutations in BRCA1 and BRCA2 also predispose to ovarian cancer, whereas mutations in BRCA2 are involved in male breast cancer and apparently in pancreatic, cervical and laryngeal cancers. However, mutation of neither gene appears to play an important role in sporadic breast cancer, implying that sporadic tumors have different etiologies of mutagenesis than those most frequently found in inherited cancers (Stratton, 1996). Jensen et al. (1996) provided conflicting evidence that BRCA1 is a protein localized in the cytoplasm and cell membrane, and is also present as a secreted protein in cell culture supernatants. The BRCA1 protein shares sequence homology and biochemical analogy with the granin family of secreted proteins, located in secretory granules, and some granin-type proteins are regulated by estrogen (Thompson et al., 1995). Moreover, the breast is an exocrine gland whose primary role is secretion. Using K-18 antibodies against BRCA1, we observed BRCA1 staining in the lumina of the ductules in normal breast demonstrating that BRCA1 proteins were present in secretions of the breast. A patient suffering from apocrine metaplasia also presented apical cytoplasmic staining and apocrine secretion staining in the lumen of the tubes with K-18 antibodies (Bernard-Gallon et al., 1998). Coene et al. (1997) reported localization of BRCA1 in the perinuclear compartment of the endoplasmic reticulum-Golgi complex and in tubes invaginating the nucleus in breast tissues. These findings account for BRCA1 being a member of the family of secreted proteins. We have detected BRCA1 and BRCA2 in the cytoplasm and/or the nucleus of cells of normal tissues, carcinomas in situ and invasive carcinomas, which is in accordance with the proposed localization of BRCA1 and BRCA2. Nevertheless, it is noteworthy that 2 patterns of nuclear staining were detected. In some breast carcinomas, the nucleus was completely stained and in others, the staining was more specifically perinuclear and more marked in Golgi vesicles located close to the nucleus, or in plaques in the cytoplasm corresponding to the endoplasmic reticulum. These 2 different patterns were found inside one same carcinoma, indicating different cell cycle steps. BRCA2 staining was also found in secretions in mammary gland ducts and in tufts of invasive carcinoma (data not shown). Based on these results, we further investigated the presence of BRCA1 and BRCA2 in milk fat globules (MFG) using immunochemical analysis with a large panel of antibodies against BRCA1 and BRCA2 (Table I). MFGs are formed by exocytosis of lipid from epithelial cells of the mammary gland and are enveloped by plasma membrane from epithelial cells. Analyses were performed on snap-frozen mammary gland samples collected from 2 children. The first (child I) died suddenly at the age of 4 weeks. At that age, the mammary gland is active and may continue to grow and secrete milk (Fig. 1a–f). The second (child II) died at the age of 5 months, when newborn breast development and milk secretion stop (McKiernan et al., 1998) (Fig. 2a–e). The last sample was from a lactating hamartoma of the breast from an 8-month term pregnant woman (Fig. 3a–g). Immunohistochemical staining of BRCA1 and BRCA2 on frozen sections from the breast of child I. (a) K-18 antibody: weak cytoplasmic staining of ducts; (b) 8F7 antibody: weak cytoplasmic staining of ducts; (c) 17F8 antibody: weak epithelial cytoplasmic staining and strong staining of MFG inside a duct; (d) 66046N: duct with strong epithelial cytoplasmic staining, while inside the lumen MFGs are detached and exhibit cytoplasmic staining (nuclei are counterstained with hematoxylin); (e) 66066E: duct with epithelial cytoplasmic staining, strong cellular apical pole staining and cytoplasmic staining of MFG in milk secretion in the lumen; (f) 66076E: cytoplasmic staining of MFG and ductal epithelium and nucleolar staining in some nuclei. Scale bars: 20 μm. BRCA1 and BRCA2 immunostaining of frozen sections from the breast of child II. (a) Control: an irrelevant first layer antibody was used; (b) K-18: BRCA1 staining is diffuse in the cytoplasm of ductal epithelium (no MFG secretion is present); (c) 8F7: duct with nuclear staining (arrowheads); (d) 66046N: strong cytoplasmic staining in duct; (e) 66076E: strong cytoplasmic staining, more intense toward the lumen, and nucleolar staining in some nuclei. Scale bars: 20 μm. Immunohistochemical localization of BRCA1 and BRCA2 on formalin-fixed and paraffin sections of a lactating breast hamartoma. (a) HES: hamartoma architecture of mammary parenchyma; (b) HES: MFG secretion in the lumen of the ducts; (c) K-18 antibody: cytoplasmic staining; (d) 17F8: nuclear staining in ductal epithelium (arrowhead) and in MFG (arrow); (e) 66046N: cytoplasmic and cellular apical pole staining of duct, and MFG staining in milk secretion; (f) 66066E: cytoplasmic staining of lactiferous ducts and staining of milk secretions; (g) 66076E: staining of milk secretions (arrowhead) inside a lactiferous duct and cytoplasmic staining of epithelium and detaching MFG. Scale bars: 100 μm (a); 20 μm (b–g). Using different antibodies against BRCA1 and BRCA2, we found that lobular ducts in the mammary gland of the 4-week-old child contained milk secretion with BRCA1 (Fig. 1c,d) and BRCA2 expression in the cytoplasm of MFG (Fig. 1e,f) as well as in the lactating hamartoma of the breast (Fig. 3d–g), for which the presence of MFG secretion is clearly visible in Figure 3b. In contrast, tissue sections of the older child's mammary gland, whose milk secretion had ceased, were devoid of MFG expressing BRCA1 (Fig. 2b–d) and BRCA2 (Fig. 2e) proteins. An exclusively nuclear staining pattern was more frequently found in mammary gland sections using the monoclonal anti-BRCA1 antibodies 8F7 (Fig. 2c) and 17F8 (Fig. 3d) raised against a glutathione-S-transferase (GST)-BRCA1 fusion protein containing amino acids encoded by a 3′ portion of BRCA1 exon 11 and by a 5′ portion of BRCA1 exon 11, respectively (Chen et al., 1995,1996a,b). Using these antibodies, Chen et al. (1995) concluded that BRCA1 is a nuclear protein of normal breast epithelial cells. We also observed nuclear staining, when using 8F7 and 17F8 antibodies, in other tissues such as colorectal tumors and corresponding normal colorectal mucosa (data not shown). Remarkably, the choice of immunogen for raising antibodies against a large-size protein such as BRCA1 is indeed essential when interpreting the results of immunohistochemistry. We did observe intense cytoplasmic epithelial and MFG staining in milk secretions using antibodies against BRCA1 (66046N; Figs. 1d, 2d, 3e) and BRCA2 (66066E; Figs 1e, 3f and 66076E; Figs. 1f, 2e, 3g) from PharMingen (San Diego, CA) whereas K-18 antibodies from Santa Cruz Biotechnology (Santa Cruz, CA) produced a lower staining intensity for BRCA1 (Figs. 1a, 2b, 3c). Nucleoli were also stained in nuclei from frozen breast sections of the 2 young children using the same anti-BRCA2 antibody (66076E; Figs. 1f, 2e). No nucleolar staining was seen in the lactating hamartoma (Fig. 3g). This may be due to differences in fixation technique (formalin fixation followed by paraffin embedding of tissues) used for the latter (Coene et al., 1997). Expression of BRCA2 protein in mammary gland nucleoli may be related to BRCA2 histone acetyltransferase activity (Siddique et al., 1998). Our results suggest a possible role of BRCA1 and BRCA2 in lactation. Yours sincerely, We are grateful to Mrs. C. Picard and Mrs. J. Avinain for technical assistance and Mr. G. Ragonnaud for figure prints. Dominique J. Bernard-Gallon*, Pierre Dechelotte*, Pascale G. Rio*, Yves-Jean Bignon Yves-Jean.Bignon@cjp.u-clermont 1.fr*" @default.
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• W2024581019 date "1999-05-31" @default.
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• W2024581019 title "BRCA1 and BRCA2 proteins are expressed in milk fat globules" @default.
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• W2024581019 doi "https://doi.org/10.1002/(sici)1097-0215(19990531)81:5<839::aid-ijc28>3.0.co;2-v" @default.
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