Context-Dependent Roles of LSD1 in Mammary Epithelial Cells and Breast Cancer
Abstract
This proposal will address the Breast Cancer Research Program overarching challenges, "identify what drives breast cancer growth; determine how to stop it," and "conquer the problems of overdiagnosis and overtreatment." It is now well known that both genetic and epigenetic events can drive breast cancer growth. Genetic events are those changes in nucleotides themselves, which are the building blocks for DNA in the cell, whereas epigenetic events refer to those chemical modifications either on proteins that surround DNA (i.e., histones) or on DNA itself. These modifications affect the accessibility of regulatory proteins to DNA and can change the way in which the genetic information embedded in the DNA sequence is interpreted. It is important to note that whereas genetic changes are irreversible, epigenetic changes are often reversible. Epigenetic changes are controlled by epigenetic regulators, which are often proteins with enzymatic activities that modify the tails of histone proteins. Because of this property, epigenetic regulators are attractive therapeutic targets for treating breast cancer (referred to as "epigenetic therapy"). In fact, therapeutic approaches based on the idea of epigenetic therapy are being developed in other types of human cancers, in particular in leukemia, which has had encouraging outcomes. However, in breast cancer, this approach has not been explored extensively. In this project, we will study one such epigenetic regulator called LSD1. LSD1 is a protein responsible for removing the methyl group from either the number 4 or number 9 lysine residue of a histone protein called histone H3. By doing this, it can either repress or activate its target gene expression, respectively. In breast cancer, it was found that LSD1 was highly expressed in those breast cancers that are negative for the expression of estrogen receptor (ER), which are typically poorly differentiated basal-like breast cancer with unfavorable prognosis. However, lab research so far has found that in some experiments, LSD1 appeared to suppress breast cancer progression and metastasis, whereas in other experiments, LSD1 seemed to promote breast cancer development. As target cells of breast cancer, there are two types of breast epithelial cells, luminal cells and basal cells. Studies in our group so far have found that LSD1 might play distinct roles in luminal and basal cells. In luminal cells, LSD1 may control their differentiation, whereas in basal cells, which include mammary stem cells, LSD1 may control the normal function of mammary stem cells. We propose that the reason why so far the role of LSD1 in breast cancer appears contradicting is because it may play distinct roles in different subtypes of breast cancers, or even at different stages during progression of breast cancer. To a certain degree, the subtype/stage-specific roles of LSD1 in breast cancer may in fact reflect its distinct roles in different subsets of normal breast epithelial cells. We further hypothesize that in well-differentiated luminal breast cancers, LSD1 may safeguard these luminal tumor cells from acquiring more malignant features by maintaining them in a differentiated state, whereas in less differentiated basal-like breast cancers, it may drive a stem cell program instead to maintain basal-like tumor cells in a malignant state. In order to develop therapeutic approaches to target LSD1 in human breast cancer, it is therefore particularly important to elucidate its role in breast cancer in a subtype and/or stage-specific manner, so that only patients with the correct type and/or stage of breast cancer would be chosen for therapy targeting LSD1. To achieve our goal, we will use mouse models to further determine differential roles of LSD1 in different subpopulations of mammary epithelial cells by conditionally disrupting its coding gene in either luminal cells or basal cells. We will also disrupt its coding gene in different subsets of ma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510100
Entities
People
- Zhe Li
Organizations
- United States Army