Define the Twist-ATX-LPAR1 Signaling Axis in Promoting Obesity-Associated Triple-Negative Breast Cancer
Abstract
Breast cancer remains the second leading cause of cancer-related death in women, with a yearly toll of more than 40,000 deaths in the United States alone. Generally, breast cancer can be divided into four major molecular subtypes, namely, Luminal A, Luminal B, HER2 overexpression, and triple-negative breast cancer (TNBC), based on the genetic profile of tumor cells. Among the four subtypes, TNBC is more aggressive and associated with poorer 5-year survival rate for two reasons: (1) Lack of early detection approaches. Tumor cells often have spread to other organs and tissues inside the body upon diagnosis. (2) Lack of efficient drugs on the market. Current treatment usually relies on combination of surgery, radiotherapy, and chemotherapy, which unfortunately has limited efficacy at the later stage of TNBC. Ample epidemiological evidence strongly indicates that premenopausal women with overweight/obesity are more vulnerable to TNBC. In a rural Appalachian population that has one of the highest obesity rates in United States, nearly 50% of TNBC is associated with obesity. The obesity rate has been increasing rapidly in the United States over recent decades, posing another daunting threat to our battle against TNBC. Our study described here aims at elucidating the mechanistic linkage between TNBC and obesity, which will provide molecular basis for the development of novel diagnostic and treatment strategies for the benefit of obese women with TNBC. Our previous study provided solid evidence that the protein Twist promotes the development of TNBC, and inhibition of Twist activity can efficiently suppress TNBC progression in a mouse model. In addition, it is known that Twist is abundantly expressed in human and mouse fat cells; mice with Twist overexpression are more subject to high-fat diet induced obesity. These findings indicate an essential role of Twist in both TNBC and obesity. Through a genome-wide approach, our study further indicates that Twist activation enhances expression of the proteins ATX and LPAR1 in TNBC cells. ATX and LPAR1 are signal-relay proteins and important accomplices for many diseases, including TNBC and obesity. In obese women with TNBC, tumor cells are usually surrounded by overgrown fat cells. We hypothesize that an abnormal Twist-ATX-LPAR1 signaling mediates the crosstalk between TNBC cells and surrounding fat cells, which would promote the development and progression of obesity-associated TNBC. The overall objective of this proposal is to clarify the function and regulation of Twist and to explore the therapeutic potential of targeting Twist-ATXLPAR1 in TNBC and obesity. Accordingly, we have carefully planned experiments with the following specific aims: (1) we will use contemporary molecular and cellular approaches to characterize how Twist regulates ATX and LPAR1 expression in TNBC cells and fat cells; (2) we will perform cell co-culture to evaluate the role of Twist-ATX-LPAR1 signaling during TNBC cell-fat cell crosstalk; and (3) we will take advantage of different mouse models to define the Twist-ATX-LPAR1 signaling in promoting obesity-associated TNBC; in addition, we will evaluate Twist activation as well as ATX and LPAR1 expression in human TNBC samples. The research proposed in this application has untapped potential for high translational impact. Upon completion of our 3-year study, we are confident to be rewarded with the following achievements. Firstly, functional characterization of Twist-ATX-LPAR1 signaling will provide new insights into the pathogenesis of obesity-associated TNBC. Secondly, we expect that Twist activation status can be used as a new surrogate biomarker for predicting the development of TNBC in obese women. Thirdly, the knowledge gained through our study may push forward the development of novel targeted therapies. Particularly, we envision that highly specific small molecules inhibiting Twist activity will become strong candidates to treat obes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610067
Entities
People
- Andrew J Morris
Organizations
- United States Army
- University of Kentucky