Grants and Contracts Details
Breast cancer remains the second leading cause of cancer-related death in women worldwide. Among the breast cancer subtypes, triple negative breast cancer (TNBC) carries a poorer prognosis, given its higher genomic instability, tendency toward early metastasis, and lack of effective targeted therapies. Epidemiological evidence strongly indicates the co-morbidities of TNBC and obesity. A better understanding of the mechanistic linkage between TNBC and obesity is crucial to the development of novel prevention and treatment strategies. TNBC intrinsically activates the epithelial-mesenchymal transition (EMT) program, during which tumor cells gain fibroblast-like properties with reduced intercellular adhesion and increased mobility. EMT mainly occurs at the tumor-stromal boundary (tumor invasive front). In obese women with TNBC, tumors are surrounded by overgrown adipose tissue (AT) with increased macrophage infiltration. The pro-inflammatory milieu may prime for aberrant signaling transduction within tumor cells to further promote EMT and metastasis. As a key EMT inducer, the transcription factor Twist is highly expressed in TNBC. We recently demonstrated that Twist is activated through di-acetylation; acetylated Twist then recruits BRD4 to co-regulate gene transcription during EMT. Pharmacological inhibition of the Twist-BRD4 interaction can suppress invasion, cancer stem cell (CSC)-like properties and tumorigenicity of TNBC cells. Intriguingly, Twist is abundantly expressed in human and mouse AT and functions to modulate lipid metabolism and energy homeostasis. These findings indicate that Twist may serve as a hub molecule mediating the development and progression of TNBC in women with obesity. To identify potential Twist target genes, we performed cDNA microarray and found the mRNA levels of Autotaxin (ATX) and LPAR1 were dramatically increased in Twist-overexpressing breast cancer cells. Encoded by the ENPP2 gene, ATX is a secreted enzyme that produces most of the extracellular lysophosphatidic acid (LPA), which signals through its receptors (LPAR1-6) to mediate a wide range of inflammatory processes including wound healing, fibrosis and metastasis. Intriguingly, AT is an important source for the synthesis and secretion of ATX, and dysregulation of ATX level/activity is involved in dietary-induced obesity, with the underlying mechanism remaining contentious. Given the tight linkage between TNBC and obesity, and the roles of Twist in mediating EMT and energy homeostasis, we propose that Twist activation intensifies the ATX-LPAR1 signaling to promote the development and progression of obesity-associated TNBC. The overall objective of this proposal is to delineate the function and regulation of Twist, and to explore the therapeutic potential of targeting Twist-ATX-LPAR1 axis in TNBC and obesity. Accordingly, we will achieve the following Specific Aims: Aim 1: Characterize the function of Twist in regulating ATX and LPAR1 expression. Our recent studies showed that Twist activation (di-acetylation) is required for its function in TNBC cells. In this proposal, we will determine whether Twist is also subject to di-acetylation in adipocytes and whether its di-acetylation correlates with adipogenic differentiation. Furthermore, we will determine whether Twist directly targets ENPP2 and LPAR1 in TNBC cells and adipocytes. Aim 2: Delineate the role of Twist-ATX-LPAR1 axis in mediating TNBC cell properties and transcriptional program. We will determine whether Twist activation intensifies the ATX-LPAR1 signaling through enhancing both autocrine and paracrine production of LPA to promote the migration, invasion and CSC-like properties of TNBC cells. In addition, we will perform cDNA microarray analyses to identify candidate genes regulated by the Twist-ATX-LPAR1 signaling axis. Aim 3: Define the Twist-ATX-LPAR1 signaling axis in promoting obesity-associated TNBC in vivo. We will firstly examine whether obesity facilitates development of TNBC. Furthermore, we will apply spontaneous metastasis model and syngeneic transplantation model to examine whether Twist-ATX-LPAR1 axis mediates diet-induced obesity, promotes tumor growth and metastasis, and increases CSC population. Finally, we will determine whether Twist activation correlates with ATX and LPAR1 expression, as well as BMI (body mass index) in archived TNBC specimens from Appalachian population. The research proposed in this application is significant and novel. Functional characterization of Twist-ATX-LPAR1 signaling will help elucidate the mechanism underlying the co-morbidities of TNBC and obesity. Application of inhibitors specifically disrupting Twist-BRD4 interaction may provide a new therapeutic approach for both of these diseases.
|Effective start/end date||4/15/16 → 4/14/20|
- Army Medical Research and Materiel Command: $585,937.00
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