ARTICLE |
Correspondence to: Jacques Simard, Lab. of Familial Cancers, CHUL Research Center, 2705 Laurier Blvd., Quebec City G1V 4G2, Canada.
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Summary |
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The breast and ovarian cancer susceptibility gene BRCA1 encodes a phosphoprotein of 1863 amino acids containing a highly conserved N-terminal RING finger domain and a C-terminal acidic region typical of several transcription factors. BRCA1 acts as a tumor suppressor that may inhibit the proliferation of breast and ovarian cancer cells. To gain knowledge and to further understand the biological function of BRCA1, we examined its localization and expression in various tissues from 20-year-old male and female cynomolgus monkeys (Macaca fascicularis) by in situ hybridization using a 35S-labeled human BRCA1 DNA probe fragment derived from exon 11. In mammary glands, BRCA1 expression was primarily located in the duct and acinar epithelial cells. In the ovary, strong BRCA1 expression was detected in granulosa cells in maturing follicles and in luteal cells of the corpus luteum, as well as in the epithelial cells overlying the tunica albuginea. Specific signal was also observed in epithelial cells of the oviduct, endometrium, cervix, and vagina. Moreover, BRCA1 was strongly expressed in the germinal epithelium of the seminiferous tubules as well as over interstitial cells of the testis, in the epithelium of the epididymis, and in epithelial cells bordering the glandular lumen of the seminal vesicles. Signal was also detected in both the anterior and posterior lobes of the pituitary. In the adrenal glands, the signal was greater in the zona glomerulosa compared to the two other cortical zones, whereas the medullary cells were weakly labeled. In the stomach, and in small and large intestine, epithelial cells of the crypts usually exhibited stronger positive reaction than that observed over surface epithelial lining cells. BRCA1 expression was also found in diverse types of epithelial cells of the thyroid, pancreas, salivary glands, trachea, urinary bladder, and kidneys. In addition to demonstrating widespread tissue- and cell-specific expression of the BRCA1 gene in primate tissues, primarily in the epithelia, we observed a weaker but specific signal in various other cell types, suggesting a generalized biological function of BRCA1. (J Histochem Cytochem 45:1173-1188, 1997)
Key Words: BRCA1, tumor suppressor gene, in situ hybridization, mammary gland, ovary, epididymis, epithelium, neoplasm genetics, transcription factors
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Introduction |
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Recently, the structure of BRCA1, a gene located on chromosome 17q21 that predisposes to breast cancer, the most common female malignancy, and ovarian cancer, the leading cause of death from gynecological malignancies, was elucidated (70 KB of genomic DNA and encodes a protein of 1863 amino acids (
Development of breast and/or ovarian tumors in linked families is associated with loss of the wild-type BRCA1 allele, which supports its predicted role as a tumor suppressor gene (
In mouse mammary gland, BRCA1 expression is induced during puberty, pregnancy, and after treatment of ovariectomized animals with estrogen and progesterone (
In situ hybridization analysis suggests that mouse BRCA1 may play a critical role in cell growth and differentiation because its transcript is expressed at 9.5 days and later stages and appears to be generally expressed throughout developing mouse embryos, primarily in rapidly proliferating cell types undergoing differentiation (
The lack of well-characterized antibodies not only significantly delayed characterization of the BRCA1 function at the molecular level but also hindered analysis of its tissue- and cell-specific expression (
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Materials and Methods |
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Animals
The 20-year-old male and 20-year-old female Macaca fascicularis were proven breeders, originating from the Philippines and maintained for 12 years at the Animal Resources Division, Sir Frederick Banting Research Center of the Health Protection Branch of Government of Canada, Ottawa, under the supervision of Dr. J. Fournier, in a facility accredited by the Canadian Council on Animal Care. Animals were exsanguinated under isoflurane anesthesia.
Histological Techniques
For in situ hybridization, the different tissues were rapidly excised without any fat and frozen on dry ice in support medium (OCT) and then kept at -80C. Ten-µm serial sections were then cut at -20C and mounted on Superfrost/Plus Microscope slides (Fisher Scientific; Montréal, PQ, Canada) and were thereafter fixed in 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4) for 10 min at 20C.
Preparation of Human BRCA1 DNA Probes
Three different DNA fragments derived from exon 11 of the BRCA1 gene were obtained after PCR amplification of human genomic DNA using the following pairs of primers: (a) 5'-CTAAGTGTTCAAATACCAGTGAAC-3' and 5'-CTG-AGTGCCATAATCAGT-ACCAGG-3'; (b) 5'-GCAGAAG-AGGAATGTGCAACA-3' and 5'-GCCTCTGAACTGAGA-TGATAG-3'; and (c) 5'-TCTATCATCTCAGTTCAGAGG-3' and 5'-ACTGGAGCC-CACTTCATTAGTAC-3'. Fragments a, b, and c correspond to nucleotides 2248-2459 (211 BP), 2751-2999 (249 BP), and 2978-3290 (313 BP), respectively, where the nucleotides refer to human BRCA1 cDNA sequence in Genbank under accession number U-14680. PCR reactions were performed using the appropriate sets of primers as described (-35S]-dCTP (Amersham; Oakville, Ontario, Canada) by the random primer method to high specific activity of 1 x 109 dpm/µg. The DNA probe fragment b was selected for the present study. It is of interest to note that the other two fragments gave identical data, thus confirming that the hybridization signal indeed corresponds to BRCA1 transcripts. In fact, the nucleotide sequence of the human probe fragment b shares 96.7% identity with the corresponding region in the cynomolgus BRCA1 gene.
In Situ Hybridization
In situ hybridization of frozen tissue sections with human BRCA1 DNA probe was adapted from previously described methods (-35S]-labeled human BRCA1 DNA fragment b/section. After hybridization, the sections were rinsed once for 1 hr with 2 x SSC (1 x SSC being 0.15 M NaCl and 0.015M Na-citrate, pH 7.0) and then processed through washes with increasing stringency to minimize the nonspecific binding as follows: 1 x SSC at 20C for 1 hr; 0.5 x SSC at 20C for 1 hr; 0.5 x SSC at 42C for 1hr; 0.5 x SSC at 20C for 1 hr; 0.1 x SSC at 20C for 30 min. In parallel, the control adjacent sections from each tissue were treated with pancreatic RNAse A (100 µg/ml; Boehringer Mannheim) for 45 min at 37C before hybridization. After these procedures the sections were dehydrated and exposed for autoradiography with Kodak X-Omat film before being coated with liquid phototographic emulsion (Kodak NTB-2; Intersciences, Markham, Ontario, Canada). The times of exposure for the tissue sections was as follows: stomach 2 days; salivary glands 3 days; ovaries and oviduct 4 days; testes, epididymis, seminal vesicles, pituitary gland, pancreas, liver, and large intestine 5 days; mammary gland, skin, uterus (body), and vagina 7 days; kidneys, small intestine, heart and thyroid gland 8 days; urinary bladder 16 days; cervix, aorta, and trachea 21 days. After indicated exposure times, the slides were developed and the sections stained with hematoxylin-eosin.
Histological Examination
Several bright- and darkfields of all tissue sections were examined by a pathologist and independently by a second observer. The measurement was done twice. Tissues were scored for BRCA1 expression and distribution on a qualitative scale as follows: -, absence of specific signal; , heterogeneous expression with less than one quarter of cells showing a specific signal;
, homogeneous expression with one to three quarters of cells showing positive signal;
, homogeneous expression with most cells showing strong positivity or grain density observed in more than three quarters. The same scoring system was applied to all tissue sections.
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Results |
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To select organs exhibiting a hybridization signal, we first observed the autoradiographic reaction occurring on X-ray films. All the organs showing a specific reaction were then processed for light microscopic autoradiography. As indicated in Table 1 and further detailed below, our findings clearly show widespread tissue distribution of the BRCA1 mRNA, which not only is strongly expressed in various epithelial cell types but is also specifically detectable, in general, to a weaker extent in several other cell types.
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Breast and Skin Tissues
As a control, we first analyzed by in situ hybridization the BRCA1 expression in normal breast tissues from an adult woman. In human mammary gland, BRCA1 mRNA was clearly expressed by acinar epithelial cells and duct epithelial cells, whereas few stromal cells were weakly labeled (data not shown). No signal was observed in sections treated with RNAse before hybridization. In close agreement with these observations, in cynomolgus monkey mammary glands the signal was almost exclusively located in the duct and acinar epithelial cells, whereas heterogeneous weak expression was found in stromal cells (Figure 1).
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In breast skin, the basal cells of the epidermis as well as keratinocytes showed a specific signal (data not shown). In the dermis, the sebaceous glands were weakly labeled (data not shown).
Female Genital System
In the ovary, strong specific hybridization signal was detected in the granulosa cells of the primary small and large secondary follicles as well as in the luteal cells of the corpus luteum (Figure 2; and data not shown). The interstitial glandular cells of the ovarian stroma were also specifically labeled, but to a lesser extent. In maturing follicles, the theca interna appeared weakly labeled (data not shown). We also noted relatively strong labeling in the epithelial cells overlying the tunica albuginea, and the ovarian cortical connective tissue was diffusely covered by silver grains (Figure 2C). As shown in Figure 2E, the epithelial cells of the oviduct exhibited a positive signal comparable to that observed over the ovarian surface epithelial cells.
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In the uterus, silver grains were observed in high concentrations over both the glandular and the luminal epithelial cells of the endometrium (Figure 3A). The connective tissue of the lamina propria-submucosa was also labeled. The smooth muscle nuclei of myometrium were weakly labeled (data not shown). In the cervix and vagina, specific hybridization signal was detected in the stratified squamous epithelial cells, and a weaker reaction was detected in the connective tissue (Figure 3C and Figure 3E).
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Male Genital System
In the testis, strong specific reaction could be detected in the germinal epithelium of the seminiferous tubules (Figure 4A). Similar data were also obtained in the rat testis using a rat BRCA1 exon 11 cDNA probe (Durocher et al., unpublished data). Very strong BRCA1 expression was primarily observed in the epithelium of the epididymis, whereas only a few silver grains could be detected over the smooth muscle cells. The spermatozoa found in the lumen of the ducts did not show any specific reaction (Figure 4C ). In the seminal vesicles the positive reaction, which was relatively weaker than that observed in the epididymis, was also mostly restricted to the epithelial cells bordering the glandular lumen (Figure 4E).
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Endocrine Organs
In the pituitary gland, all the cells of the anterior lobe appeared to express BRCA1 mRNA. In the posterior lobe, a lower number of dispersed cells, most likely corresponding to pituicytes, were covered with silver grains (Figure 5A). In the thyroid gland, the hybridization signal was detected in the follicular epithelium and the C-cells (Figure 5C). In the endocrine pancreas, most of the islets showed strong labeling (data not shown). In the adrenal glands, strong homogeneous BRCA1 expression was observed in the zona glomerulosa of the cortex (Figure 5G). Moreover, cells of the two other cortical zones, i.e., zona fasciculata and zona reticularis, were also specifically labeled, although the signal was weaker than in the zona glomerulosa. Medullary cells were poorly but specifically labeled (data not shown).
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Digestive System
In the stomach, strong BRCA1 mRNA expression was observed over the epithelial cells of the mucosal gastric glands, whereas the lamina propria did not appear specifically labeled (Figure 6A). In the small intestine, the glandular epithelium of the mucosa was strongly labeled, whereas the lamina propria and smooth muscle exhibited a weak reaction (Figure 6C). In the tubular glands of the colon, the epithelial cells showed a strong signal but the lamina propria and the muscularis mucosa exhibited a very weak reaction (Figure 6E).
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In the liver, all the hepatocytes were covered with a few silver grains, whereas the biliary duct cells were poorly labeled (data not shown). In the exocrine pancreas, the acinar cells showed a strong signal and the ductal cells were covered by only a few silver grains (Figure 5E). In the salivary glands, both acinar and duct epithelial cells were moderately labeled (data not shown).
Urinary System
In the bladder, the transitional urinary epithelium was homogeneously labeled, and a weak reaction was detected over smooth muscle cells (Figure 7A). The connective tissue did not show any specific reaction (Figure 7A). In the kidney, the tubule epithelial cells, as well as the glomeruli, were specifically labeled with the same intensity (Figure 7C).
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Other Tissues
In the heart muscle, the nuclei of the cardiac myocytes were strongly covered by silver grains, whereas the muscle fibers exhibited no specific labeling (Figure 7F). The endocardial and aortic endothelial cells exhibited weak specific staining (data not shown).
In the trachea, the respiratory epithelium in contact with the airway was strongly labeled (Figure 7G). The glandular epithelium also exhibited specific labeling, which appeared weaker than that observed over the respiratory epithelium.
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Discussion |
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The present study demonstrates widespread tissue- and cell-specific expression of the BRCA1 transcript in adult male and female cynomolgus monkey tissues. BRCA1 mRNA is primarily expressed in a large variety of epithelia in tissues derived from the ectoderm, endoderm, and mesoderm. Nevertheless, a weak but specific signal was also observed in various other cell types. Our data are therefore in close agreement with the tissue distribution of BRCA1 mRNA expression in adult mouse as measured by Northern analysis (
In this regard, there is evidence that BRCA1 may have a role in the control of recombination and in the maintenance of genome integrity, thus suggesting that a loss of its function might result in genomic errors and the subsequent activation of checkpoint genomic guardian functions, the outcome of which might be cell-cycle arrest (
The existence of mRNA splice variants of BRCA1 expressed in normal tissues, cell lines, and tumors from various tissues, including breast, ovary, lung, and colon, was recently demonstrated (11b lacking most of exon 11 (positions 908-4215) was localized in the cytoplasm instead of the nucleus and appears to have a distinct putative role because its overexpression is not toxic to the cells, in contrast to the full-length BRCA1 protein (
In cynomolgus monkey mammary glands, BRCA1 mRNA expression was almost exclusively located in the duct and acinar epithelial cells, whereas heterogeneous weak expression was found in stromal cells. This observation is in agreement with the findings that BRCA1 is primarily expressed in human and mouse normal mammary epithelium, as revealed by in situ hybridization (
The pattern of BRCA1 expression in the monkey ovary, showing a predominant expression in granulosa cells in developing follicles and relatively lower levels in stromal cells, is in agreement with the data obtained in adult mouse ovary. Moreover, we have also shown in maturing follicles that the theca interna is weakly labeled, whereas relatively strong BRCA1 expression is found in luteal cells of the corpus luteum. It will be of interest to study whether the expression of BRCA1 in these cell types may be hormonally regulated.
Our original observation of relatively strong labeling found in the epithelial cells overlying the tunica albuginea of the ovary is in contrast to the lack of BRCA1 mRNA expression described in murine ovarian epithelium (
BRCA1 expression in the monkey testis is predominantly observed in seminiferous tubules. This observation is in close agreement with our analysis in the rat testis showing a strong expression in primary spermatocytes and spermatids, whereas no specific labeling was detected in mature sperm cells (Durocher 1995). In the mouse testis, however, it was possible to detect a signal in all cell layers except the extreme periphery of the tubule (
In the present study, we have also found for the first time a very strong BRCA1 expression in the epithelium of the epididymis, whereas in the seminal vesicles its expression, which is relatively weaker than that observed in the epididymis, is almost solely restricted to the epithelial cells bordering the glandular lumen. This finding is also consistent with the predominant BRCA1 expression in epithelial cells.
Our analysis clearly demonstrates the relatively high levels of BRCA1 expression in epithelia of the stomach and of the small and large intestine. In general, in these tubular organs of the gastrointestinal tract, cells of the crypts, known to contain rapidly dividing, undifferentiated progenitor cells, exhibited a stronger positive reaction than that observed over surface epithelial lining cells. In agreement with our observation, it has been reported that in the mouse gastrointestinal tract BRCA1 expression is primarily confined to the basal epithelial cell layer located at the base of the mucosal epithelium and intestinal crypts (
Although BRCA1 mRNA was predominantly detectable in the epithelia of all the tissues analyzed, we have also demonstrated a weak but specific signal in several other cell types, including stromal cells of both male and female genital systems, in smooth muscle cells in various tissues, and in cardiac myocytes as well as in fibroblasts, thus illustrating a more generalized function of BRCA1 in primate tissues. The present data therefore provide a novel insight that may aid in the further understanding of the biological role of BRCA1 in normal tissues and how its dysfunction may be involved in malignant transformation in breast and ovarian tissues.
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Acknowledgments |
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Supported by the Medical Research Council (MRC) of Canada and by Endorecherche. FD is recipient of a Studentship from the MRC and JS is an FRSQ scholar.
We thank Dr Jim Gourdon for his expert assistance.
Received for publication September 10, 1996; accepted March 25, 1997.
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