The squamous cell carcinoma antigen (SCCA) was identified initially as a serological marker of more advanced squamous cell carcinomas (SCC). The protein exists in two isoforms -- neutral and acidic -- of equivalent molecular mass. Both forms of SCCA are detected normally in squamous epithelium, the bronchial mucosa and ductal epithelium of the breast. The SCCAs are also detected in well-differentiated squamous cell carcinomas and breast carcinomas in situ, but not in poorly-differentiated squamous cell or invasive breast carcinomas. Although the function of SCCA is unknown, the cloning and squence analysis of the cDNA suggests that this molecule is a member of the superfamily of high-molecular weight serine-proteinase inhibitors (serpins). The serpins regulate diverse biologic functions including fibrinolysis, clot-formation, tumor invasiveness and cell survival. Surprisingly, the molecular cloning and physical mapping of the squamous cell carcinoma antigen gene from normal human genomic DNA revealed the presence of two genes. They are tandemly arrayed within 18q21.3 and flanked by two other closely related serpins, plasminogen activator inhibitor type 2 (PAI2) and maspin. The genomic structure of the two genes, SCCA1 and SCCA2 is highly conserved. Based on the deduced amino acid sequences (92 percent identical), calculated pIs, and preliminary expression studies, the investigators hypothesize that SCCA1 and SCCA2 are expressed normally in epithelia lining the skin, mucous membranes, bronchi and breast; inhibit different proteinases; encode for the neutral and acidic """"""""isoforms"""""""" of SCCA, respectively; and modulate the invasiveness of breast and possibly squamous carcinoma cells. Based on these hypotheses, the long-term objectives of this proposal are two-fold: to understand the normal biologic function of SCCA1 and SCCA2 and to determine whether aberrant expression of these proteins plays a role in the pathogenesis of epithelial-derived tumors especially invasive ductal carcinomas of the breast.
The specific aims designed to accomplish these goals are to determine: 1) the relative patterns of SCCA1 and SCCA2 expression in both normal and malignant cells. 2) whether SCCA1 and SCCA2 are inhibitory-type serpins, 3) whether SCCA1 and SCCA2 encode for the neutral and acidic forms of SCCA, and 4) whether SCCA1 or SCCA2 expression can suppress or enhance different aspects of the transformed phenotype.
Showing the most recent 10 out of 13 publications
