FOXP2 as a Master Regulator of Basal-Like Breast Cancer Initiation and Progression and a Novel Target for Antineoplastic Therapy
Abstract
Background: The spread of breast cancer occurs in >90% of breast cancer patients, but is the least understood component of cancer biology. A better understanding of how metastatic dissemination manifests would reveal critical components of this process and would help develop new therapeutic strategies that save patients lives. Recent advances in cancer research have indicated that cancer cells within tumors exist within a hierarchy in which only a small subset of cells is able to spread and give rise to metastatic growths in secondary organs. These highly malignant cancer cells, which behave like stem cells for new cancers and are dubbed "cancer stem cells" or CSCs, have been shown to possess increased resistance to therapeutics and are thought to be the root cause underlying cancer recurrence and malignancy. Specific Aims: Using a model of breast cancer we have recently developed, we identified a novel molecular pathway that regulates the generation, propagation, and maintenance of metastatic CSCs. We found that this pathway converges on and inhibits a gene expression regulator called FOXP2. Importantly, we found that inhibition of FOXP2 is sufficient in promoting CSC propagation and metastasis and that it represents a characteristic feature of clinically advanced breast cancers and poor patient survival. Here, we will elucidate how FOXP2 silencing promotes malignancy using in vitro and in vivo animal models, determine whether restoration of FOXP2 expression in metastases leads to their regression in preclinical animal systems, and inhibit the molecular addictions of FOXP2-silenced cancer cells in the context of metastasis management in pre-clinical setting. Overarching Challenges: FOXP2 is known as a speech-associated gene involved in language development in humans, but its connection to breast cancer pathogenesis has not been previously made. Our data strongly indicate that FOXP2 downregulation is the focal point of multiple pro-tumorigenic and pro-metastatic triggers and suggest that it represents a critical node that is necessary for breast cancer pathogenesis. Therefore, characterization of the activities and functions of FOXP2 as a major tumor/metastasis suppressor will stand to (1) identify what drives breast cancer growth; determine how to stop it and (2) identify why some breast cancers become life-threatening metastasis. Additionally, our proposed studies will test the feasibility of reversing FOXP2 inhibition using preclinical cellular and animal models, therefore offering new translational methodologies to manage metastatic disease and (3) eliminate the mortality associated with metastatic breast cancer. Translational Ramifications: The characterization of novel determinants of breast cancer relapse and therapy resistance will provide critical insights into the fundamental mechanisms behind breast-cancer-associated mortality. The success of our proposed aims will have a number of translational outcomes: (1) provide proof-of-principle preclinical evidence that supports the efficacy of restoring FOXP2 as a means combat metastatic disease, (2) provide proof-of-principle preclinical evidence that supports the repurposing of existing MYC and HER2 inhibitors in the management of a subclass of triple-negative breast tumors that presently has few targeted therapies, (3) provide the groundwork for the use of tumoral FOXP2 expression levels as a novel prognostic indicator to identify the patient populations who will benefit from therapy, and (4) establish whether restoration of FOXP2 expression sensitizes metastatic disease to existing chemotherapies. Extended to the clinic, this will have significant bearing on reducing the toxicity and morbidity associated with advanced disease. Although we consider much of our proposed studies to be preclinical, the success of our project will provide the data necessary for the development or re-purposing of therapies that can be advanced into phase-graded
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510386
Entities
People
- Antoine E Karnoub
Organizations
- Beth Israel Deaconess Medical Center
- United States Army