Abstract B54: Squamous cell carcinoma antigen 1 (SCCA1) promotes mammary tumorigenesis through the induction of misfolded protein stress

Abstract

Abstract SCCA1, a member of the serine/cysteine protease inhibitor family, is upregulated in several cancers such as the cervix, lung, head and neck, liver, skin, and breast, and has been used as a diagnostic/prognostic marker. However, the biological function of SCCA1 in tumorigenesis remains largely unclear. Here we show that ectopic expression of SCCA1 in the non-tumorigenic mammary epithelial cell line MCF10A leads to spindle shaped cell morphology, increased cell migration, resistance to anoikis, foci formation in soft agar, as well as orthotopic tumor formation in immune-compromised mice. Gene expression analysis revealed that SCCA1 induces changes that are associated with epithelial-mesenchymal transition (EMT). Mechanistically, SCCA1 interferes with cellular protein homeostasis leading to a heightened unfolded protein response including the nuclear translocation of the transcriptionally active form of ATF6α. This increased ATF6α signaling results in NF-κB activation and increased pro-inflammatory response including an IL-6 autocrine signaling loop that drives EMT and transformation. These findings indicate a previously unknown role of SCCA1 in promoting tumorigenesis by inducing misfolded protein stress, NF-κB activation, and pro-tumorigenic cytokine signaling. Citation Format: Namratha Sheshadri, Erica Ullman, Joseph Catanzaro, Ji-An Pan, Emily Chen, Wei-Xing Zong. Squamous cell carcinoma antigen 1 (SCCA1) promotes mammary tumorigenesis through the induction of misfolded protein stress. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B54.