Anti-SH3GL2 monoclonal antibody, clone 6B7

Head and neck squamous cell carcinoma (HNSCC) is the most common and fatal cancer type in India with about 30-40% of frequency. Molecular etiologies of the disease include consumption of alcohol, tobacco habit and HPV infection. The lack of understanding in molecular pathogenesis of the disease leads to poor survival of HNSCC patients. Cytogenetic analysis has shown that the chromosomal abnormalities gradually increase with progression of the tumor in a non-random manner. Molecular analysis of-copy number variation, promoter methylation, mutation and expression (gene and protein) revealed identification of some of the candidate tumor suppressor genes located in the chromosomal 3p, 8q, 9p/q, 11q, 13q and 17p etc. regions associated with development of HNSCC. These genes are further seen to control different cellular pathways like-(1) frequent inactivation of SH3GL2 and CDC25A-associated with EGFR homeostasis and de-phosphorylation respectively; (2) Rb and p53 associated pathways in G1-S cell cycle transition; (3) Slit-ROBO associated signaling pathways; (4) PTCH associated Hedgehog signaling; (5) DNA repair pathways like-mismatch and double strand break repair; (6) apoptosis and (7) integrin signaling. Now, systemic approach has been taken to characterize the molecular pathways in this tumor to find out the key regulatory steps for management of the disease.

Purpose: The goal of this study was to understand the role of altered mitochondrial function in breast cancer progression and determine the potential of the molecular alteration signature in developing exosome-based biomarkers. Experimental Design: This study was designed to characterize the critical components regulating mitochondrial function in breast tumorigenesis. Experiments were conducted to assess the potential of these molecules for exosome-based biomarker development. Results: We observed a remarkable reduction in spontaneous metastases through the interplay in mitochondria by SH3GL2, vesicular endocytosis-associated protein and MFN2, an important regulator of mitochondrial fusion. Following its overexpression in breast cancer cells, SH3GL2 translocated to mitochondria and induced the production of superoxide and release of cytochrome C from mitochondria to the cytoplasm. These molecular changes were accompanied by decreased lung and liver metastases and primary tumor growth. SH3GL2 depletion reversed the above phenotypic and associated molecular changes in nontumorigenic and tumorigenic breast epithelial cells. Loss of SH3GL2 and MFN2 expression was evident in primary human breast cancer tissues and their positive lymph nodes, which was associated with disease progression. SH3GL2 and MFN2 expression was detected in sera exosomes of normal healthy women, but barely detectable in the majority of the women with breast cancer exhibiting SH3GL2 and MFN2 loss in their primary tumors. Conclusions: This study identified a new mitochondria reprogramming pathway influencing breast cancer progression through SH3GL2 and MFN2. These proteins were frequently lost in breast cancer, which was traceable in the circulating exosomes. (C) 2016 AACR.