The role of Breast Cancer Antiestrogen Resistance 3 (BCAR3) in triple-negative breast cancer growth and progression
Arras, Janet, Microbiology - School of Medicine, University of Virginia
Bouton, Amy, MD-MICR Microbiology, University of Virginia
Breast cancer is the second most common cause of cancer-related deaths in women and constitutes a group of diseases that exhibit heterogeneity. Despite diagnostic and therapeutic advances, challenges remain to improve the clinical care of patients. Breast cancer subtypes have been identified based on the hormone receptor status and molecular profile of tumors. Understanding the characteristics of each subtype is important to help inform therapeutic strategies and improve patient outcomes. Triple-negative breast cancer (TNBC) is a subtype that makes up 10-20% of all breast cancer cases and has the worst 5-year survival rate. This subtype is characterized as lacking immunohistochemically detectable expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC typically presents with aggressive, high-grade lesions and is more prevalent among black women of African descent. Previous work from our group and others showed that the adaptor molecule Breast Cancer Antiestrogen Resistance 3 (BCAR3) together with Cas and Src, promotes breast cancer cell migration and invasion. The work presented in this thesis focuses on identifying the role of BCAR3 in TNBC growth and progression. Using in vivo and in vitro approaches, the data presented in this thesis demonstrate that BCAR3 promotes TNBC tumor growth, proliferation, and migration. Our studies show that BCAR3 protein expression is elevated in patient-derived breast cancer tumor samples and in TNBC cell lines, and elevated BCAR3 mRNA levels are associated with poor outcomes in patients with TNBC. This work is the first to report that BCAR3 regulates TNBC tumor growth in mouse orthotopic xenograft models. Our data also show that BCAR3 is a regulator of MET signaling and that BCAR3-MET coupling has a functional role in TNBC.
As a follow up to these findings, studies were undertaken to understand the role of BCAR3-MET coupling in basal-like TNBC. Using biochemical approaches, preliminary data are presented showing that basal-like TNBC cells with reduced BCAR3 expression exhibit elevated levels of MET receptor expression and phosphorylation. Conversely, when BCAR3 was over-expressed in a basal-like cell line with low endogenous levels of BCAR3, MET receptor levels and phosphorylation were reduced. These changes were not observed in claudin-low TNBC cells, suggesting that BCAR3 may regulate MET signaling differently based on the genetic background of TNBC. Future studies are needed to determine the functional significance of these findings.
Finally, preliminary studies are presented using computational approaches to investigate the transcriptional landscape regulated by BCAR3 in TNBC cells. Differential gene expression analysis on cells cultured on plastic, matrigel, and in mouse mammary epithelial cell organoids showed that BCAR3 regulates a broad set of genes and pathways. While the expression of 33 genes was impacted by loss of BCAR3 under all three conditions, a subset of the pathways regulated by BCAR3 in TNBC cells cultured on plastic was distinct from those in cells cultured in 3D matrigel. Validation as well as functional studies are needed to make conclusions about the transcriptional networks regulated by BCAR3.
The data presented in this thesis indicate that BCAR3 is an important promoter of TNBC growth and may serve as a valuable biomarker and/or therapeutic target to improve the clinical care of patients with TNBC in this age of precision medicine. Future studies are required to explore how BCAR3 serves to integrate signals that promote aggressive tumor phenotypes to maximize targeting of functional BCAR3 signaling nodes.
PHD (Doctor of Philosophy)
Breast Cancer Antiestrogen Resistance 3 (BCAR3) , Triple-negative breast cancer (TNBC), Growth and progression
All rights reserved (no additional license for public reuse)