Breast Carcinoma-associated Fibroblasts Share Similar Biomarker Profiles in Matched Lymph Node Metastasis.

This study sought to understand the role of breast carcinoma-associated fibroblasts in the progression of cancer cells into lymph nodes. We compared fibroblasts of primary tumors and matched the involved lymph nodes to select fibroblast activation markers, namely α-smooth muscle actin (α-SMA), S100A4, and vimentin, as well as to determine the frequency of transforming growth factor ß1, a pleiotropic cytokine that induces the differentiation of fibroblasts to myofibroblasts, and its downstream effectors: CXCR4 and p-AKT. We disposed samples of 80 primary invasive ductal carcinomas and matched the involved lymph nodes from 43 cases into 3 tissue microarrays, and analyzed stromal and tumor epithelial cells separately by immunohistochemistry. Control uninvolved lymph nodes were analyzed by whole-tissue sections. Cancer-associated fibroblast in lymph nodes with macrometastasis expressed similar profiles of vimentin, α-SMA, and S100A4 as those found in primary tumors. Cancer-associated fibroblast were uniformly estrogen receptor, progesterone receptor, HER-2, Ki-67, and p53 negative, but expressions of transforming growth factor ß1 (TGFß1), CXCR4, and p-AKT staining (62.3%, 52.4%, 65%, respectively) were equivalent between primary and lymph node metastasis (LNM) fibroblasts. A significant coexpression of TGFß1 with p-AKT and CXCR4 in LNMs suggested the involvement of these proteins with TGFß1 signaling. These biomarkers, including α-SMA and S100A4, were negative in fibroblasts of cancer-free lymph nodes, with the exception of vimentin. Our finding that expressions of biological markers were similar in fibroblasts of the primary tumors and in matched LNMs, but were absent in cancer-free lymph nodes, supports the assumption that the lymph node stroma mimics the microenvironment observed in primary tumors.

C-kit immnunohistochemical expression in breast carcinomas and lymph node metastasis. Lack of prognostical significance and review of literaturei

Objective: To evaluate the expression of c-kit in breast invasive ductal carcinomas (IDC) and metastasis to lymph nodes considering epithelial and stromal components separately and correlate this variable to others clinical, pathological and biological markers (EGFR, Her-2, ER, PR, Ki-67 and p53 expression). Methods: We analysed 80 IDC, stage T2-T4 Nx Mx, in TMA of epithelial, stromal component and lymph nodes. Statistical analysis considered significant a p value < 5%. Results: c-kit expression was founded in 9 cases in epithelial component (11.3%) and in 10 cases (12.5%) of stromal component. The 43 samples of lymph nodes metastasis were negative. EGFR and Her-2 were predominantly negative, both in epithelial (77.5% and 73.75%, respectively), as stromal (97.5% and 95.0%) components and metastasis to lymph nodes (83.7% and 62.8%). While ER, PR, Ki-67 and p53 were positive in 49 (61.0%), 40 (53.0%), 67 (83.75%) and 59 cases (73.75%) in the epithelial component. Stromal cells have proved negatives. c-kit epithelial expression correlated to presence of in situ component (p = 0.044) and stromal c-kit expression correlated to presence of necrosis (p = 0.002). There was no association between c-kit expression and staging and biological markers. Transformed epithelial cells at me lymph nodes metastasis stained for ER, PR, Ki-67 and p53 in 27 (62.8%), 16 (37.5%), 41 (95.0%) and 28 cases (65.1%), respectively. Conclusions: The expression of c-kit is mostly negative in primary IDC both in the epithelial and stromal component, as well as in lymph node metastasis. The lack of correlation between c-kit and others tyrosine kinase proteins suggest that they are independently regulated. Metastasis for Iymph nodes were not c-kit positive and further studies of mutations of c-kit and his family, correlate with other prognostic factors and survival required to reveal the exact mechanism of action of this molecule in breast cancer.

Objetivo: Avaliar a expressão de c-kit em células epiteliais, estromais e metástases para linfonodos de carcinomas ductais mamários invasivos (CDI) e correlacionar essa variável com os outros marcadores clínicos, patológicos e biológicos (EGFR, HER-2, RE, RP, Ki-67 e p53). Métodos: Analisaram-se 80 CDI, estádios T2-T4 Nx Mx, em TMA de componente epitelial, estromal e linfonodos. O valor de p < 5% foi considerado significante. Resultados: A expressão de c-kit foi encontrada em 9 casos no componente epitelial (11,3%) e em 10 casos (12,5%) do componente estromal. As 43 amostras de metástases para linfonodos foram negativas. EGFR e Her-2 foram predominantemente negativos, tanto em epitélio (77,5% e 73,75%, respectivamente), como estroma (97,5% e 95,0%) e metástases para linfonodos (83,7% e 62,8%), enquanto RE, RP, Ki-67 e p53 foram positivos em 49 (61,0%), 40 (53,0%), 67 (83,75%) e 59 casos (73,75%) no componente epitelial. Células do estroma se mostraram negativas. A expressão de c-kit epitelial correlacionou-se com a presença do componente in situ (p = 0,044) e a expressão de c-kit no estroma se associou com a presença de necrose (p = 0,002). Não houve associação entre a expressão de c-kit com estadiamento e marcadores biológicos. Células epiteliais transformadas de metástases para linfonodos coraram para RE, RP, Ki-67 e p53 em 27 (62,8%), 16 (37,5%),41 (95,0%) e 28 casos (65,1%), respectivamente. Conclusões: A expressão de c-kit é majoritariamente negativa em CDI primário tanto no componente epitelial quanto no estromal, assim como em metástases linfonodais. A falta de correlação entre o c-kit e outras proteínas tirosina quinases sugere que elas sejam reguladas de forma independente. Metástases para linfonodos não foram positivas para c-kit, e estudos posteriores de mutações do c-kit e sua família, correlacionando com outros fatores prognósticos e sobrevida, são necessários para revelar o exato mecanismo de ação dessa molécula no câncer de mama.

Role of the expression of the tyrosine kinase receptor kit in invasive ductal carcinomas of the breast: a review

Given the necessity to research new variables that identify greater disease-free survival, through appropriate therapeutic intervention among patients of the same treatment subgroup, it is necessary to find promising candidates for prognostic factors in breast cancer. Among the tyrosine kinase receptors, we can mention the membrane receptor termed c-KIT, overexpressed in gastrointestinal stromal tumors. Normal ductal breast cells and benign breast tissue highly express the c-KIT protein, while an accentuated reduction of same was observed in samples of breast cancer, varying from non-metastatic primary carcinomas to carcinomas with distant metastasis. The study analyses the literature specific to c-KIT protein expression in breast tumors, indicating that the immunohistochemical expression of c-KIT is mainly negative in stroma of primary breast neoplasms or not specifically cited, and with controversial results regarding the epithelial component. Subsequent studies of mutations of the proto-oncogene c-KIT and correlation with other prognostic factors and survival are necessary to reveal the exact action mechanism of this molecule in breast cancer.