Triple Negative Breast Cancers (TNBC), if considered its own disease, would rank as the fifth or sixth leading cause of cancer deaths in women in the USA. The only treatment option for these patients is multi-agent chemotherapy, and TNBC tumors are highly variable in terms of their chemotherapy sensitivity. TNBC is also known to be biologically heterogeneous, with multiple possible subtypes present. We hypothesize that much of this apparent heterogeneity actually represents cellular plasticity, and that some forms of heterogeneity can actual morph from one form into another; for example, in vitro and in vivo results show that within basal-like cell lines, claudin-low-like cells exist and can inter-convert nto the more differentiated basal-like epithelial state. We propose to test this plasticity hypothesis using in vivo models by identifying some of the genetic determinants that drive cells into the basal-like state (which is more chemotherapy sensitive), and that maintain TICs in basal-like cancers using both genetically engineered mouse (GEM) and patient derived xenograft (PDX) models. In addition, we will compare the response to standard of care therapies in the primary tumor versus a metastatic site (i.e. lung), and evaluate changes in TICs using unique signaling pathway-based reporters.
Breast cancer is the most frequent type of cancer that occurs in women (>200,000 cases/year) and accounts for ~40,000 deaths each year in the United States. In part through our own gene expression profiling studies, breast cancer is now appreciated as being composed of multiple genetically unique subtypes with different etiologies and outcomes. Triple Negative Breast Cancers are an important clinical subtype of breast cancer because they lack the three known important therapeutic targets used in the breast cancer clinic, namely the Estrogen Receptor, the Progesterone Receptor, and the HER2 protein. In addition, we and others have shown that TNBC are more frequent in African Americans (AA), which partially explains outcomes disparity difference seen for AA in the USA. From a therapeutic perspective, TNBC patients only systemic treatment option is chemotherapy. Importantly, we do know that many TNBC patients respond well to chemotherapy, and thus for many, this is an effective treatment. In this application, we propose study directly the chemotherapy responsiveness of TNBC and explore the hypothesis that much of the resistance seen is due to intra-tumoral heterogeneity and the tumor's ability to change from one type of cellular 'differentiation state' into a more resistant 'state'. If this hypothesis is found to be tue, then we will have identified a mechanism of drug resistance, and found the key pathways and genes for which additional therapeutic interventions might be able to overcome these resistance effects.
|Tanioka, Maki; Mott, Kevin R; Hollern, Daniel P et al. (2018) Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer. Genome Med 10:86|
|Zhao, Na; Cao, Jin; Xu, Longyong et al. (2018) Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J Clin Invest 128:1283-1299|
|Couture, Heather D; Williams, Lindsay A; Geradts, Joseph et al. (2018) Image analysis with deep learning to predict breast cancer grade, ER status, histologic subtype, and intrinsic subtype. NPJ Breast Cancer 4:30|
|Matsunuma, Ryoichi; Chan, Doug W; Kim, Beom-Jun et al. (2018) DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer. Proc Natl Acad Sci U S A 115:E11978-E11987|
|Nguyen, Tuan M; Kabotyanski, Elena B; Dou, Yongchao et al. (2018) FGFR1-Activated Translation of WNT Pathway Components with Structured 5' UTRs Is Vulnerable to Inhibition of EIF4A-Dependent Translation Initiation. Cancer Res 78:4229-4240|
|An, Yeji; Adams, Jessica R; Hollern, Daniel P et al. (2018) Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast. Cell Rep 25:702-714.e6|
|Siegel, Marni B; He, Xiaping; Hoadley, Katherine A et al. (2018) Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer. J Clin Invest 128:1371-1383|
|Thomas, Clémence; Henry, Whitney; Cuiffo, Benjamin G et al. (2017) Pentraxin-3 is a PI3K signaling target that promotes stem cell-like traits in basal-like breast cancers. Sci Signal 10:|
|Witek, Ma?gorzata A; Aufforth, Rachel D; Wang, Hong et al. (2017) Discrete microfluidics for the isolation of circulating tumor cell subpopulations targeting fibroblast activation protein alpha and epithelial cell adhesion molecule. NPJ Precis Oncol 1:|
|Mehta, Gaurav A; Parker, Joel S; Silva, Grace O et al. (2017) Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer. Breast Cancer Res Treat 162:439-450|
Showing the most recent 10 out of 50 publications