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. 2018 Dec 17:2018:8120579.
doi: 10.1155/2018/8120579. eCollection 2018.

Loss of BRCA1 Spontaneously Induces the Tumorigenesis in Lacrimal Gland

Sun Eui Kim  1 , Hye Jung Baek  1 , Eun Jung Park  1 , Sung Chul Lim  2 , Sang Soo Kim  1
Affiliations

Loss of BRCA1 Spontaneously Induces the Tumorigenesis in Lacrimal Gland

Sun Eui Kim et al. Anal Cell Pathol (Amst). .

Abstract

Environmental and genetic factors exert important influences on lifespan and neoplastic transformation. We have previously shown that spontaneous tumors form frequently in mice homozygous for a full-length Brca1 deletion. In general, mutations of BRCA1 are closely associated with induction of breast and ovarian cancers but are also known to contribute to the incidence of other cancers at a low frequency. Female Brca1-mutant mice (Brca1co/coMMTV-cre) were generated by crossing Brca1 conditional knockout mice and MMTV-cre mice, and the occurrence of lacrimal gland abnormalities and tumors was followed until mice reached 18 months of age. Lacrimal gland tumors, which occur at a very low frequency in the human population (1 per 1,000,000 per year), were detected in 7 cases of Brca1co/coMMTV-cre mice (2.75%) older than 9 months of age. None of seven mice exhibited any abnormality in the mammary gland including neoplasia, suggesting lacrimal gland tumor is spontaneously and independently formed. These tumors, which were detected in seven mutant mice that displayed exophthalmoses, were malignant, originated from epithelial cells, and were identified as acinic cell carcinoma by pathological analysis. Further analysis revealed that tumorigenesis was accompanied by the accumulation of cyclin D1 and decreased expression of the cellular oncogenes, c-Myc, c-Jun, and c-Raf. Tumors also exhibited rearrangement of cytoskeletal proteins, including β-catenin, keratin 5, and vimentin, depending on tumor progression. These results suggest that BRCA1 is involved in genetic stability of the lacrimal gland, providing new insight into genomic instability in organism maintenance and tumorigenesis of the lacrimal gland.

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Figures

Figure 1
Figure 1
Abnormal eye phenotypes in Brca1co/coMMTV-cre mice. (a–d) Brca1co/coMMTV-cre mice that developed tumors at 9 (a), 16 (b), 17 (c), and 10 (d) months of age. Top: the mice exhibited exophthalmoses, protrusions around the eye, and opaque eyeballs. Bottom: dissected eyes and eye-associated tumors from the corresponding Brca1co/coMMTV-cre mice. (e) Representative MR scan image of Brca1co/coMMTV-cre mouse that developed a tumor at 10 months of age. Lacrimal tumor (indicated by arrow) side was expanded to the eye region while eye (e) in other side was intact. (f) Targeting construction of Brca1 deletion by cre recombinase. P1, P2, and P3 represent the primers for detection of targeted mutation and deletion. (g) PCR analysis against Brca1 using primers as indicated by the numbers. PCR products specific for Brca1 knockout (P1/P3) were detected in lacrimal tumors but not in normal lacrimal gland.
Figure 2
Figure 2
Identification of lacrimal gland tumors in Brca1co/coMMTV-cre mice. (a–c) Low-power view of H&E-stained sections of the 16 (a), 17 (b), and 9 (c) months of age cases of retrobulbar tumors (asterisks) separated by skeletal muscles (arrows) in the eyeballs (E). Nonneoplastic lacrimal glands (N) adjacent to the tumors are evident. The panels at the right are magnifications of the boxed areas in the adjacent panels. Scale bars: 1 mm.
Figure 3
Figure 3
Histological analysis of lacrimal tumors in Brca1co/coMMTV-cre mice. (a) High-power view of an H&E-stained section of the 9 months of age case (Figure 2(c)) shows acinic cell carcinoma (asterisk), characterized by variable-sized cystic spaces lined by simple or stratified cuboidal epithelium with some papillary projections. Yellow lines separate the tumor (asterisks) and nonneoplastic lacrimal gland (N). The retrobulbar tumor is separated from the eyeball (E) by the skeletal muscle. (b) Higher-magnification view of the boxed area. Variable vacuolated, clear tumor cells mimicking adjacent nonneoplastic serous acinar cells of the lacrimal gland were found. (c) A poorly differentiated, predominantly solid component with a scant glandular pattern is noted in an H&E-stained section of the 17 months of age case (Figure 2(b)). Scale bars: 200 μm.
Figure 4
Figure 4
Overexpression of cyclin D1 and increased cell proliferation in lacrimal gland tumors from Brca1-mutant mice. (a) Protein expression patterns in lacrimal gland tumors (T1 (10 M), T2 (11 M), T3 (12 M), and T4 (14 M)) from Brca1co/coMMTV-cre mice compared with the normal tissue (N1, N2, N3, and N4). β-Actin was used as a loading control. (b–j) Lacrimal gland sections from tumor areas of Brca1co/coMMTV-cre mice stained with H&E (b, e, h) and immunostained for PCNA (c, f, i) and cyclin D1 (d, g, j). Yellow lines in (c) and (d) separate tumor (T; upper left) and normal (N; lower right) tissue. Scale bars, 200 μm.
Figure 5
Figure 5
Alteration of skeletal protein distribution in lacrimal gland tumors of Brca1-mutant mice. Distribution of β-catenin, keratin 5, and vimentin in normal (N; lower right) and tumor-containing (T; upper left) regions (a, c, e) and well-differentiated (W; lower left) and poorly differentiated (P; upper right) regions (b, d, f) of a lacrimal gland. Scale bars: 100 μm.
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