Breast cancer is the leading malignancy among women in the United States and can be divided into two major histological subtypes, invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). Though very different in histological appearance, on a molecular level, and in progression, both IDC and ILC are primarily treated with endocrine therapies. Unfortunately, ILC tumors have shown evidence for therapy resistance through late recurrences and metastases. Further, ILC has been chronically understudied, enhancing the rationale to study the molecular mechanisms that underlie ILC progression so that we may better generate targeted therapeutics for this patient subset. This project focuses on understanding the role of epithelial to mesenchymal transition transcription factors (EMT-TFs), such as Snail, in driving the unique phenotypes observed in ILC. Snail is known to down regulate expression of E-cadherin, an epithelial marker that is characteristically lost in ILC. Loss of E-cadherin contributes to linear growth of ILC cells and to more mesenchymal and metastatic phenotypes. Interestingly, Snail has also been noted to have upregulated expression in ILCs compared to IDCs. Additionally, Snail was recently noted to interact with epigenetic proteins such as lysine specific demethylase 1 (LSD1), controlling expression of genes such as E-cadherin. Thus, understanding this interaction, what it means to progression in the disease and knowing how we can target this may potentially provide new therapeutics for ILC patients. To understand the Snail/LSD1 axis and its role in ILC progression, I will utilize molecular biology approaches to globally identify which genes are regulated by this axis. Gene regulation will be confirmed in endocrine resistant settings. Further, expression of Snail/LSD1 and downstream signaling components will be analyzed in clinical samples with expression correlated to patient survival and outcome. Also, I will study the phenotypic implications of growing ILC cells in different growth environments, including a novel in vitro model that I am currently developing. This model will employ micropatterned extracellular matrix proteins in wells of growth plates, forcing ILC cells to grow in a linear fashion as they do in vivo. This model will be the first faithful recapitulation of in vivo ILC cell growth. Successful completion of this project will establish the importance of targeting the Snail/LSD1 axis in ILC, assist in understanding the role of this axis in clinical samples, and will provide a new in vitro environment in which to grow cancer cells. Collectively, these findings will provide novel information on a potential mechanism behind the EMT-like phenotype of ILC and a new potential set of targets for this patient subset.

Public Health Relevance

Breast cancer is the leading cancer diagnosis in women in the United States with two major histological subtypes of disease including invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). Though clearly different both histologically and molecularly, IDC and ILC are treated similarly with endocrine therapies. The proposed study seeks to define epithelial to mesenchymal transition transcription factors (EMT-TFs), such as Snail, as targets in ILC patients in faithfully recapitulating growth models; understanding the importance of these targets as drivers for endocrine therapy resistance will enable a more personalized approach to treatment and prevention of progression and metastasis of this unique subset of tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA203055-02
Application #
9326810
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213