involucrin and Breast-Neoplasms

The process of human embryonic mammary development gives rise to the structures in which mammary cells share a developmental lineage with skin epithelial cells such as keratinocytes. As some breast carcinomas have previously been shown to express high levels of involucrin, a marker of keratinocyte differentiation, we hypothesised that some breast tumours may de-differentiate to a keratinocyte-derived 'evolutionary history'. To confirm our hypothesis, we investigated the frequency of involucrin expression along with that of Brk, a tyrosine kinase expressed in up to 86% of breast carcinomas whose normal expression patterns are restricted to differentiating epithelial cells, most notably those in the skin (keratinocytes) and the gastrointestinal tract. We found that involucrin, a keratinocyte differentiation marker, was expressed in a high proportion (78%) of breast carcinoma samples and cell lines. Interestingly, tumour samples found to express high levels of involucrin were also shown to express Brk. 1,25-dihydroxyvitamin D3, a known differentiation agent and potential anti-cancer agent, decreased proliferation in the breast cancer cell lines that expressed both involucrin and Brk, whereas the Brk/involucrin negative cell lines tested were less susceptible. In addition, responses to 1,25-dihydroxyvitamin D3 were not correlated with vitamin D receptor expression. These data contribute to the growing body of evidence suggesting that cellular responses to 1,25-dihydroxyvitamin D3 are potentially independent of vitamin D receptor status and provide an insight into potential markers, such as Brk and/or involucrin that could predict therapeutic responses to 1,25-dihydroxyvitamin D3.

Topics: Breast Neoplasms; Calcitriol; Cholecalciferol; Female; Humans; Neoplasm Proteins; Protein-Tyrosine Kinases; Receptors, Calcitriol

Invasive micropapillary carcinoma of the breast is a distinct variant of breast cancer. In the present study, we analyzed potential immunophenotypic changes in invasive micropapillary carcinoma.. Specimens from 15 patients with invasive micropapillary carcinoma were analyzed using clinicopathological and immunohistochemical methods. We also examined the relationship between clinicopathological factors using the Ki-67 labeling index.. Immunohistochemical staining for cytoplasmic p63 expression was seen in four (27%) tumors, and p63 nuclear expression was also observed in four (27%) tumors. Involucrin and 34betaE12 were expressed in the invasive micropapillary carcinoma component of nine (60%) and four (27%) tumors, respectively. Cytokeratin 5/6 was expressed in three (20%) tumors and cytokeratin 14 staining was negative in all tumors. In one tumor (case 3), vimentin, epithelial membrane antigen and cytokeratin 8/18 were co-expressed. Four tumors (27%) were negative for the estrogen receptor/progesterone receptor/HER2. However, 11 out of 15 (73%) tumors were positive for the estrogen receptor. The Ki-67 labeling index was significantly higher in cases with p63 tumor expression than in those without (P < 0.0001), and also higher in cases with lymph node metastasis than in cases without (P = 0.0029).. Nuclear expression of p63, involucrin and 34betaE12 were detected indicating squamous differentiation. Cytoplasmic p63 expression was also identified. The fact that the Ki-67 labeling index was significantly higher in such cases may have been associated with the aggressive behavior of these tumors. Our findings suggest that the characteristic morphology of invasive micropapillary carcinomas may be due to immunophenotypical and oncogenic changes.

Topics: Breast Neoplasms; Carcinoma, Papillary; Cell Nucleus; Cytoplasm; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Membrane Proteins; Middle Aged; Neoplasm Invasiveness; Protein Precursors; Staining and Labeling

Although breast carcinomas are considered to originate from glandular epithelial cells, some exhibit 'squamoid features', comprising stratification with a gradient in the nuclear-cytoplasmic ratio within individual cancer cell nests on microscopy. In parallel with a histological review of squamoid features, we immunohistochemically investigated the expression of involucrin, a marker of terminal squamous differentiation, in 223 breast carcinomas with one to three regional nodal metastases but no distant metastases and analysed their association with other clinicopathological parameters to explore their clinical and biological implications. Squamoid features and involucrin expression, detected in 22% and 27% of cases respectively, correlated with each other and were associated with high-grade atypia, a solid-nest pattern, cancer cell necrosis on histology and negative oestrogen receptor status. The incidence of regional recurrences was higher in patients with involucrin expression, whereas bone metastases were less frequent in groups with squamoid features or with diffuse (> or = 10%) involucrin expression. Both squamoid features and involucrin expression, which were considered to be derived either from differentiation into keratinocytes or from some kind of cellular degeneration caused by high turnover rate, are suggested to influence the biological behaviour of breast cancer cells in vivo, and they may be effective in predicting the most likely recurrence sites.

Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Squamous Cell; Cell Differentiation; Female; Humans; Immunohistochemistry; Necrosis; Neoplasm Recurrence, Local; Protein Precursors

The expression of involucrin, a structural component of the envelope of mature squamous epithelium, was studied in 166 paraffin-embedded breast carcinomas. In 41 cases (24.7%) involucrin-positive, light microscopically non squamous tumour cells were detected. The number of involucrin-positive tumour cells varied considerably from case to case. For further characterization, involucrin-positive cases were studied using monoclonal antibodies to various cytokeratins (PKK1, EAB 903, EAB 904) and, in selected cases, double immunostaining with antibodies to cytokeratins and involucrin were performed. Coexpression of involucrin and cytokeratins demonstrated by PKK1 was seen in all tumour cells, whereas coexpression of involucrin and cytokeratins detected by EAB 904 was only seen in single and scattered cells in a few cases. Cytokeratins detected by EAB 903 were not coexpressed with involucrin in our cases. Our results indicate heterogeneity of cytokeratins in breast carcinomas and suggest a dissociation in the regulation of involucrin and cytokeratin expression.

Topics: Breast Neoplasms; Carcinoma; Female; Humans; Immunohistochemistry; Keratins; Male; Protein Precursors

Extramammary Paget disease appears in anogenital, axillary, or other areas. In this study, the authors addressed the question of whether the histogenesis of 35 cases of Paget disease arising at different sites was the same.. Specimens of 35 cases of extramammary Paget disease (16 genital; 9 invasive carcinomas of genital; 6 axillary; 1 periumbilical; and 3 perianal), 4 cases of mammary Paget disease, 4 cases of breast carcinomas, and 6 cases of anal carcinomas of perianal spread from primary rectal adenocarcinomas were retrieved and stained by the avidin-biotin-complex method, using various kinds of monoclonal antikeratin antibodies.. There was no significant difference in cytokeratin expression among these cases of extramammary Paget disease. Simple epithelial keratins were expressed in Paget cells in extramammary Paget disease, but no expression of differentiation-specific or noncornifying stratified squamous epithelial keratins was observed, regardless of the degree of invasion. Paget cells in extramammary Paget disease revealed a similar cytokeratin expression to that in secretory cells of normal apocrine or eccrine glands. In addition, there was no significant difference in cytokeratin expression in tumor cells among extramammary and mammary Paget disease, breast carcinomas, and anal carcinomas.. Cases of Paget disease arising at different locations could not be distinguished from each other based on cytokeratin expression. In addition, antikeratin antibodies against simple epithelial keratins were demonstrated to be more useful for the identification of Paget cells in the paraffin sections than were conventional antibodies, such as an antibody against carcinoembryonic antigen (CEA).

Topics: Antibodies, Monoclonal; Breast Neoplasms; Carcinoembryonic Antigen; Carcinoma; Eccrine Glands; Gene Expression Regulation, Neoplastic; Humans; Keratins; Neoplasm Invasiveness; Paget Disease, Extramammary; Paget's Disease, Mammary; Protein Precursors; Urogenital Neoplasms

Involucrin, a component of the cornified cell envelope, is expressed specifically in differentiating keratinocytes of stratified squamous epithelia. To explore the regulation of involucrin expression, 3.7 kb of upstream sequences of the human involucrin gene was cloned into a plasmid containing a beta-galactosidase reporter gene and transfected into early passage keratinocytes and a variety of human cell types. The full-length construct gave maximal and tissue-specific expression. Deletion analysis showed that sequences between 900 and 2500 bp upstream of the transcriptional start site and the intron located between the transcriptional and translational start sites were required for maximal expression. Further analysis of the intron indicated that its effects on expression were independent of it being present in nascent RNA and suggested that sequences within the intron have regulatory activity. These results suggest that the involucrin intron operates in vivo to regulate expression in the epidermis.

Topics: beta-Galactosidase; Breast Neoplasms; Cells, Cultured; Epidermis; Fibroblasts; Gene Expression Regulation; Genes; HeLa Cells; Humans; Introns; Keratinocytes; Organ Specificity; Promoter Regions, Genetic; Protein Precursors; Recombinant Fusion Proteins; RNA, Messenger; Sequence Deletion; TATA Box; Tumor Cells, Cultured

Twenty-one cases of Paget's disease have been studied using histochemical, ultrastructural, and immunohistochemical methods. Eight of the tumors involved the nipple, and 13 were extramammary (11 vulvar and two anal). The antibodies used were directed against different classes of cytokeratin proteins, epithelial membrane antigen, carcinoembryonic antigen, gross cystic disease fluid protein-15, and S-100 protein. The findings of this study provide conclusive evidence that Paget's cells, regardless of their location, are adenocarcinoma cells. Intracytoplasmic mucin is scanty in Paget's cells within the nipple, but typically plentiful in the extramammary sites where the cells are frequently signet-ring cells. The common mechanism for the evolution of Paget's disease is extension of cells from an underlying carcinoma, but the possibility that some cases, particularly in the vulva, develop from intraepithelial precursors cannot be excluded.

Topics: Antibodies, Monoclonal; Anus Neoplasms; Apolipoproteins; Apolipoproteins D; Breast Neoplasms; Carcinoembryonic Antigen; Carcinoma, Intraductal, Noninfiltrating; Carrier Proteins; Female; Glycoproteins; Humans; Keratins; Membrane Proteins; Membrane Transport Proteins; Mucin-1; Paget Disease, Extramammary; Paget's Disease, Mammary; Protein Precursors; S100 Proteins; Vulvar Neoplasms