BRCA1 and γH2AX as independent prognostic markers in oral squamous cell carcinoma.

Oral squamous cell carcinomas (OSCC) are believed to originate from sequential mutations that can develop as a consequence of genetic instability acquired over time. BRCA1 are linked to DNA recombination and repair processes, being of importance for its role in regulation of RAD51 and H2AX (γH2AX). The aim of this study was to investigate the relationship between BRCA1 expression status and evaluate its prognostic impact. We selected from 150 OSCC patients, and evaluated BRCA1 expression in OSCC by immunohistochemistry and qRT-PCR, comparing its expression with homologous recombination markers (RAD51, γH2AX and p53), clinicopathological and survival data. Expression of BRCA1 was observed in 61 cases (43.88%) and was related to tumor size (T stage) (p=0.001), and gender (p=0.017). mRNA from BRCA1 showed a borderline relationship with perineural invasion (p=0.053). BRCA1 [p=0.030; HR: 2.334 (C.I.: 1.087-5.012)], γH2AX [p=0.045; HR: 0.467 (C.I.: 0.222-0.628)] and gender [p=0.001; HR: 10.386 [(C.I.: 2.679-10.623)] were independent prognostic factors for DSS. BRCA1 and γH2AX expression by OSCC cells are associated with reduced overall survival time, independent of other variables in patients, as well as gender, and our findings shed some light about DSB markers in OSCC and its role as prognostic factors.

Primary mucoepidermoid carcinoma of the breast: a case report with immunohistochemical analysis and comparison with salivary gland mucoepidermoid carcinomas.

Mucoepidermoid carcinomas in mammary glands represent 0.3% of all breast tumors. Features of salivary gland mucoepidermoid carcinoma have been used in studies concerning mucoepidermoid carcinomas of the breast because both share similar morphologic and molecular features. We report a case of primary mucoepidermoid carcinoma of the breast with an immunohistochemistry staining panel. We verified that MUC5AC occurs in more than 50% of high-grade tumors, and MUC1 correlates with shorter disease-free survival. The comparative analysis of mucin profiles may provide further insights into the clinical behavior of these tumors.

Relationship between B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) and homologous recombination regulatory genes in invasive ductal breast carcinomas.

B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) is a Polycomb group protein that is able to induce telomerase activity, enabling the immortalization of epithelial cells. Immortalized cells are more susceptible to double-strand breaks (DSB), which are subsequently repaired by homologous recombination (HR). BRCA1 is among the HR regulatory genes involved in the response to DNA damage associated with the RAD51 protein, which accumulates in DNA damage foci after signaling H2AX, another important marker of DNA damage. Topoisomerase IIIß (topoIIIß) removes HR intermediates before chromosomal segregation, preventing damage to cellular DNA structure. In breast carcinomas positive for BMI-1 the role of proteins involved in HR remains to be investigated. The aim of this study was to evaluate the association between BMI-1 and homologous recombination proteins. Using tissue microarrays containing 239 cases of primary breast tumors, the expression of Bmi-1, BRCA-1, H2AX, Rad51, p53, Ki-67, topoIIIß, estrogen receptors (ER), progesterone receptors (PR), and HER-2 was analyzed by immunohistochemistry. We observed high Bmi-1 expression in 66 cases (27.6%). Immunohistochemical overexpression of BMI-1 was related to ER (p=0.004), PR (p<0.001), Ki-67 (p<0.001), p53 (p=0.003), BRCA-1 (p= 0.003), H2AX (p=0.024) and topoIIIß (p<0,001). Our results show a relationship between the expression of BMI-1 and HR regulatory genes, suggesting that Bmi-1 overexpression might be an important event in HR regulation. However, further studies are necessary to understand the mechanisms in which Bmi-1 could regulate HR pathways in invasive ductal breast carcinomas.

The role of tumor hypoxia in MUC1-positive breast carcinomas.

Mucin 1 (MUC1) is a glycoprotein that is expressed on apical cell membranes in a variety of normal tissues. MUC1 is involved in cell signaling, inhibition of cell-cell and cell matrix adhesion, apoptosis, proliferation, and transcription. Hypoxia is an important factor that promotes cancer metastasis and stimulates angiogenesis and tumor progression. Hypoxia inducible factor 1 (HIF-1α) and carbonic anhydrase IX (CAIX) are two molecules that are involved in this process. The role of hypoxia in MUC1+ invasive ductal breast carcinomas is not well established. In this study, the expression of MUC1 was correlated with the hypoxia-associated markers HIF-1α and CAIX, as well as several immunohistochemical markers and clinicopathologic features of prognostic significance in 243 invasive ductal carcinomas. MUC1 was overexpressed in 37.0% of patients and correlated with the expression of estrogen receptor (p = 0.0001), progesterone receptor (p = 0.0001), HIF-1α (p = 0.006), VEGF (p = 0.024), and p53 (p = 0.025). In breast cancer, MUC1 expression has been associated with increased degradation of inhibitor of NF-κB (IκBα), driving NF-κB to the nucleus and blocking apoptosis and promoting cell survival. We analyzed NF-κB expression in MUC1+ breast carcinoma and found a very significant relationship between these proteins (p = 0.0001). Our findings indicate that MUC1 may play a role in the regulation of hormone receptors by increasing the inactivation of p53 and targeting NF-κB to the nucleus. Our data also support the notion that activation of HIF-1α in MUC1+ breast carcinomas may modulate VEGF expression, allowing a metabolic adaptation to hypoxia.

Carcinoma mucinoso invasor da mama e seus diagnósticos diferenciais em biópsia por agulha grossa: revisão da literatura / Mucinous invasive carcinoma of the breast and its differential diagnosis by core biopsy: review of the literature

A biópsia por agulha grossa (BAG), ou core biopsy, é uma técnica utilizada para retirar pequenos cilindros de tecido mamário. Além de lesões palpáveis, o desenvolvimento de técnicas radiológicas acuradas de localização de lesões mamárias difundiu o uso da BAG como primeira abordagem histológica de lesões não palpáveis. O diagnóstico diferencial do carcinoma mucinoso com lesões mucinosas benignas por BAG pode ser desafiador, principalmente se a lesão apresentar extravasamento de mucina. A acurácia do diagnóstico nesses casos é de extrema relevância para determinar o tipo de procedimento a ser realizado e o tratamento a ser seguido. Este estudo traz revisão e atualização da literatura sobre carcinoma mucinoso invasor da mama e seus diagnósticos diferenciais, com ênfase nos desafios para diagnóstico por intermédio da BAG. Entre os diagnósticos diferenciais estão alterações fibrocísticas com mucina luminal, lesões mucinosas papilares e mucocele-símile (que variam desde as benignas até aquelas associadas a hiperplasia ductal atípica e carcinoma ductal in situ). Alterações mucinosas também podem ser encontradas em uma variedade de lesões, como fibroadenoma e tumor phyllodes, adenoma pleomórfico e mucinose nodular. Conclui-se que a BAG é uma técnica confiável para diagnóstico de carcinoma mucinoso da mama e seus diagnósticos diferenciais, porém, em casos de dúvida ou de escassez de material, é prudente realizar biópsia excisional para melhor esclarecimento do diagnóstico.

The needle core biopsy is a technique applied to remove small cylinders of breast tissue. The development of accurate radiological techniques for location of breast lesions has spread the use of core biopsy as the first histological approach to non-palpable lesions. The differential diagnosis of mucinous carcinoma and benign mucinous lesions by core biopsy may be challenging, mainly when the lesion shows mucin extravasation. The accuracy of diagnosis in these cases is extremely important to determine the type of procedure to be performed, as well as the treatment choice. This study shows a review and an update of the literature as to invasive mucinous carcinoma of the breast and its differential diagnosis, with emphasis on the challenges of diagnosis by core biopsy. Among the differential diagnoses are fibrocystic changes with luminal mucin, mucinous papillary lesions, mucocele-like lesions that range from benign to those associated with atypical ductal hyperplasia and ductal carcinoma in situ. Mucinous changes may also be found in a variety of lesions such as fibroadenoma, phyllodes tumor, pleomorphic adenoma and nodular mucinosis. In conclusion, core biopsy is a reliable technique for the diagnosis of mucinous carcinoma of the breast and its differential diagnosis, however, in doubtful cases or when the sample is scarce, it is advisable to perform an excisional biopsy to clarify the diagnosis.