Background/Rationale: It is estimated that approximately 316,000 women will be newly diagnosed with breast cancer in the United States (U.S.) each year, and 40,000 women will die of breast cancer this year alone. Basal-like breast cancer accounts for 15-20% of all diagnosed breast cancer depending on patient population. These patients are commonly known as triple negative breast cancer because most cases often lack expression of estrogen receptor ? (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). The absence of PR, ERa, and HER-2 commonly found in basal-like breast cancer leads to these patients unlikely to respond to hormone therapies or HER-2 targeted therapies. Thus, basal-like breast cancer is highly aggressive, and often results in lung and brain metastasis. Understanding risk factors for basal-like breast cancer invasion and metastasis is urgently needed for identification of novel and specific molecular targets. Because women represent the fastest growing demographic in the US Veteran population, breast cancer is an increasingly significant public health issue for the Veterans Health Administration. Our proposed studies will investigate the transition from early-stage basal-like breast cancer to invasive breast cancer. Objectives: Palmitic acid is one of the predominant saturated fatty acids in the western diet. The goal of this study is to determine how high-palmitic acid (HPA) intake acts as a risk factor to facilitate basal-like breast cancer invasion. Based on our preliminary studies, we hypothesize that HPA increases the endothelial lipase ( LIPG) activity, which is a key driver of invasive progression in early-stage basal-like breast cancer. We also hypothesize that HPA initiates defective myoepithelial cell differentiation or loss of the mature myoepithelium, which allows tumor cell invasion. Methods:
Specific Aim 1 will examine how HPA converts quiescent LIPG-negative tumor cells into LIPG-positive tumor-initiating cells for early-stage basal-like breast cancer invasion.
Specific Aim 2 will investigate how LIPG signaling pathways contribute to loss of normal myoepithelial cell function in HPA conditions. We have initiated studies screening natural compounds combined with computational drug discovery approaches, and identified a potent LIPG inhibitor DDL-1.
Specific Aim 3 will determine if inhibition of LIPG prevents early-stage basal-like breast cancer to invasive breast cancer progression in HPA conditions. We have developed a new nanoparticle-based drug delivery system to deliver DDL-1 into mammary myoepithelial cells and tumor cells. We will use mouse models of early-stage basal-like breast cancer to study the effect of DDL-1 administration on the incidence of invasive breast cancer and circulating tumor cells in HPA conditions. Results: By identifying a mechanism by which breast cancer invasion occurs, we are hopeful that we can design a novel chemoprevention solution to inhibit tumor invasion, and therefore reduce the number of Veterans dying of advanced or metastatic breast cancer.
The current Veteran population in the U.S. and Puerto Rico is approximately 22 million; of these, nearly 200,000 female Veterans will be diagnosed with breast cancer during their lifetimes. Of those people who succumb to basal-like breast cancer, nearly all die because of the spread of breast cancer outside the breast. The goal of this proposal is to reduce breast cancer mortality. The proposed studies will investigate how the enzyme endothelial lipase LIPG contributes to the progression of early-stage basal-like breast cancer to invasive breast cancer. We will determine how LIPG facilitates the spread of breast cancer. Preliminary data strongly demonstrated this study?s feasibility. The proposed studies have the potential to provide meaningful findings that can be translated to a clinical setting.
