Carnitine Palmitoyltransferase 1A in Breast Cancer
Abstract
One of the most fundamental changes in cancer is the development of the so-called ?lipogenic phenotype,? whereby rapidly dividing tumor cells depend on their own ability to synthesize lipids (fats) as building blocks of cell membranes. This phenomenon, however, does not explain the fact that obesity is a well-known risk factor for breast cancer and many other types of malignancies. Recently emerging evidence suggests that cancer cells not only display the lipogenic phenotype but also show an increased ability to oxidize (consume) fatty acids (basic unit of fat) through a process called fatty acid oxidation (FAO) to provide bio-energy (ATP) to malignant cells. A potential role of FAO in cancer provides a mechanistic link between obesity and increased risk and mortality of breast cancer. In light of its fat-rich microenvironment, breast cancer represents one of the most relevant cancer models to investigate the oncogenic functions of FAO. FAO occurs in a cellular organelle called the mitochondrion. Fatty acids must be transported into the mitochondrial matrix to be oxidized to generate ATP. The whole process is controlled by the rate-limiting enzyme on the mitochondrial membrane called carnitine palmitoyltransferase 1A (CPT1A), which is responsible for shuttling long-chain fatty acids into the mitochondrion. In our preliminary studies, we found CPT1A protein is abundantly expressed in breast cancer cell lines and in primary invasive ductal carcinomas. Overexpression of CPT1A correlates strongly with poor survival of breast cancer patients. Inactivation of CPT1A with gene silencing or specific inhibitors causes growth suppression and reduction in intracellular ATP, suggesting that breast cancer cells rely constitutively on FAO to support malignant growth. This ?FAO-addicted phenotype? of cancer cells could offer a therapeutic window to distinguish cancer from normal tissues where FAO is only conditionally required. Our further preliminary work identifies a novel role for CPT1A in maintenance of breast cancer stem cells (CSCs), a rare subpopulation of cells responsible for cancer initiation, metastasis, recurrence, and resistance to chemo- and radiation therapies. In further support of the translational potential of CPT1A intervention, FAO is upregulated in breast cancer cells treated with the chemotherapeutic drugs doxorubicin and paclitaxel. Inhibition of CPT1A sensitizes breast cancer cells to doxorubicin and prevents CSCs from escaping the chemotherapeutic agent. We therefore hypothesize that CPT1A is a critical mediator of breast cancer development, stem cell functions, cytoprotection, and metastasis. Intervention of CPT1A could have profound effects on these malignant features of breast cancer. We will test the hypothesis through three specific aims to elucidate the mechanisms underlying the requirement of CPT1A for cell proliferation and stem cell functions (Aim 1); to explore the therapeutic potential of FAO intervention (Aim 2); and to determine the functional relevance of the endogenous Cpt1a gene to the initiation, phenotypic maintenance, and metastasis of mammary tumors in mice (Aim 3). The proposed studies fit well with the overarching challenges of the Breast Cancer Research Program ?Identify what drives breast cancer growth; determine how to stop it? and ?Identify why some breast cancers become metastatic.? In sum, these studies will establish novel oncogenic functions of CPT1A and the mechanisms linking CPT1A to malignant features of breast cancer. The inducible Cpt1a-deficient mouse model will provide a definitive answer to the role of the Cpt1a gene in the development, maintenance, and metastatic progression of the disease. Demonstration of anti-tumor effectiveness of FAO intervention alone or in combination with chemotherapies in immunocompetent mice will validate the FAO pathway as a novel anti-cancer target for both the bulk of tumor cells and the more challenging CSCs. If proved ef
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710317
Entities
People
- Xianjun Fang
Organizations
- United States Army
- Virginia Commonwealth University