Type
Text
Type
Dissertation
Advisor
Zong, Wei-Xing | Brown, Deborah | Hayman, Michael J | Chen, Emily | Crawford, Howard.
Date
2014-12-01
Keywords
Breast, cancer, EMT, IL-6, SCCA, UPR | Molecular biology
Department
Department of Molecular and Cellular Biology.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/76499
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
SCCA1 is a member of the serine/cysteine protease inhibitor (serpin) family whose intracellular targets include lysosomal cathepsins L, S and K. Its expression correlates with resistance to cell death resulting from lysosomal membrane permeabilization and cathepsin release in response to radiation and chemotherapy. Elevated SCCA1 expression has been reported in a wide array of cancers including squamous cell carcinomas of the lung, head and neck, skin, cervix, as well as hepatocellular carcinoma. Our laboratory recently found that increased expression of SCCA1 also correlates with high-grade, poorly differentiated breast carcinoma and poor prognosis. However, despite SCCA1's clear relevance in human cancer, its molecular and biological function remain largely unclear. In my dissertation research, I find that ectopic expression of SCCA1 in the non-tumorigenic mammary epithelial cell line MCF10A leads to epithelial-mesenchymal transition (EMT), a key molecular program that is co-opted by invasive and metastatic cancer cells. Correlatively, SCCA1 leads to oncogenic transformation in cultured cells as well in tumor xenografts. Silencing of endogenous SCCA1 in multiple breast cancer cell lines led to attenuation of cell growth. Mechanistically, SCCA1 interferes with cellular protein homeostasis resulting in a persistent yet sub-lethal level of endoplasmic reticulum stress leading to the activation of the unfolded protein response (UPR). This chronic stress results in NF-κ B activation and induces the production of pro-inflammatory cytokines such as interleukin-6 (IL-6) that drives EMT and oncogenic transformation. In the MMTV-Neu mouse mammary tumor model, expression of SCCA1 leads to an invasive phenotype with an exaggerated stress response and immune cell infiltration. These findings uncover a previously unknown role for SCCA1 in promoting tumorigenesis by inducing UPR, NF-κ B activation, and pro-tumorigenic cytokine production. | 106 pages
Recommended Citation
Sheshadri, Namratha, "Squamous Cell Carcinoma Antigen 1 (SCCA1) promotes mammary tumorigenesis by inducing the Unfolded Protein Response (UPR) and IL-6 signaling" (2014). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2412.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2412