Abstract P5-04-09: Squamous Cell Carcinoma Antigen 1 (SCCA1) Upregulation Causes Epithelial to Mesenchymal Transition (EMT) and Promotes Mammary Tumorigenesis

Abstract

Abstract SCCA1, a member of the family of serine protease inhibitors, was first identified as a serological marker for cervical cancer but has since been shown to be upregulated in several other cancers including lung, head and neck, liver, skin, and breast. SCCA1 is believed to protect cells from unscheduled cathepsin release and activation upon lysosomal injury. In order to understand the molecular role of SCCA in cancer, we ectopically expressed it in the immortalized yet non-tumorigenic mammary epithelial cell line MCF10A. Expression of SCCA1 impairs the efficiency of lysosomal as well as proteasomal protein degradation pathways. Transcriptional profiling of SCCA expressing cells by microarray demonstrates an altered gene expression pattern that resembles EMT. Phenotypically, SCCA1 expression leads to spindle shaped cell morphology, increased migratory potential, resistance to anoikis, and the ability to form colonies in soft agar. SCCA1-expressing MCF10A cells can form tumors when injected into the mammary fat pad of immune-compromised mice. Correlative to the transforming activity, SCCA1 expressing cells have enhanced Erk and Akt signaling pathways, and have bypassed the requirement of growth factors and hormones that are essential for proliferation of MCF10A cells. In a transgenic mouse model, where SCCA1 is conditionally expressed in mammary epithelial cells under the control of MMTV promoter, increased mammary gland ductal branching and hyperplasia are observed. These findings indicate a previously unknown role of SCCA1 in promoting EMT and tumorigenesis, possibly by inducing chronic misfolded protein stress that contributes to enhance tumor-promoting signaling. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-04-09.