Correlation between BRCA1 expression and clinicopathological factors including brain metastases in patients with non-small-cell lung cancer.

BACKGROUND: Previously identified as a breast and ovarian cancer susceptibility gene, BRCA1 has gained major scientific interest as a potential prognostic and/or predictive marker for various tumors, including non-small-cell lung cancer (NSCLC), the leading cause of cancer related mortality worldwide. BRCA1 plays a central role in DNA damage response (DDR. It undergoes phosphorylation by various DDR kinases at different serine residues, of which ser1524 is known to be specifically phosphorylated by ATM in response to genotoxic stress. METHODS: We performed BRCA1 immunohistochemistry on several tissue microarrays (TMAs) of 113 early (I, II stage) and advanced (III, IV stage) NSCLCs, using MS110 antibody against the BRCA1 N-terminal and S1524 antibody against the phosphorylated form of BRCA1 protein at ser1524 (Abcam). Patients with III and IV stage disease were treated by adjuvant cisplatin-based chemotherapy. Staining results were correlated with overall survival (OS), disease free survival (DFS) and with the occurrence of brain metastases. RESULTS: BRCA1 S1524 nuclear positivity was significantly correlated with longer OS and DFS in stage I and II patients (P<0.05), while OS and DFS were shorter in S1524 positive stage III and IV patients (P<0.05). No significant correlation was found with brain metastases. CONCLUSION: The results show that BRCA1 phosphorylaton, at least in ser1524, differentiates the fate of early and advanced NSCLC as well as response to chemotherapy, but the underlying mechanisms are not completely understood. Detection of phosphorylated forms of BRCA1 might serve as a useful prognostic and predictive marker for patients with NSCLC.

The immunohistochemical expression of BNIP3 protein in non-small-cell lung cancer: a tissue microarray study.

Drug resistance is one of the reasons for chemotherapy failure in non-small-cell lung carcinoma (NSCLC). One of the major mechanisms of drug resistance is the inhibition of chemotherapy-induced apoptosis. Therefore, the study of novel cell death pathways could possibly enable us to overcome resistance to apoptosis in NSCLC. One of the non-caspase types of cell death is autophagy. BNIP3 protein, a Bcl-2 family member, highly expressed in some tumours, plays a key role in the induction of autophagy. In the present study, we investigated the immunohistochemical expression and subcellular localization of BNIP3 in a series of early- and late-stage non-small-cell lung carcinomas and normal bronchial tissues, and correlated this expression with the occurrence of metastasis and survival. BNIP3 was strongly expressed in the nucleus of cancer cells in 16/79 (20.3%) cases. This BNIP3 positivity did not correlate with histological grade, stage, histology type, metastatic potential, or expression of BNIP3 according to median values. No significant correlation was observed between the expression of BNIP3 and the overall survival of NSCLC patients (p = 0.55). Nor did we find any significant correlation between BNIP3 expression and the occurrence of site-specific metastasis (p = 0.85).