Role of FANCA in Breast Tumorigenesis and Cancer Development
Abstract
One of the most predominant hallmarks driving human breast cancer is genome instability. It creates genome-wide diversity that enables cells to acquire additional capabilities required for cancer development and progression. Given the critical role of DNA double-strand break (DSB) repair in maintaining genome stability and preventing tumorigenesis, elucidating how cells direct the repair of DSBs has significant clinical implications. A successful example for exploiting defects in DSB repair is the induction of synthetic lethality by use of PARP inhibitors in patients with BRCA deficiency. DSBs are highly cytotoxic DNA lesions, which can lead to cell death or mutagenic consequences that drive genome instability and tumorigenesis. Indeed, disruption of many DNA DSB repair genes predispose to breast cancer, including mutations in BRCA1 and BRCA2. DSBs are repaired by an error-free homologous recombination (HR) pathway and three error-prone pathways, single-strand annealing (SSA), microhomology-mediated end joining (MMEJ), and non-homologous end joining (NHEJ)), that introduce genome instability in cells. We recently identified a novel role of FANCA in promoting the error-prone SSA repair of DSBs and genome instability. Our preliminary data demonstrate that the expression level of FANCA is associated with breast cancer progression and inversely correlates with patient distant metastasis-free survival. In addition, inactivating FANCA in a triple-negative breast cancer (TNBC) cell completely abolishes breast cancer formation in mice. More importantly, we found that a natural compound, Withaferin A (WFA), at a non-toxic dose, targets FANCA for degradation, disables error-prone SSA, and leads to effective killing of the TNBC cells by a synthetic lethality mechanism. In this proposal, we hypothesize that the pathologically high expression of FANCA tips the balance of DNA repair in the favor of an error-prone pathway promoting genome instability and eventually driving tumorigenesis and development of breast cancer. Furthermore, we hypothesize that targeting FANCA with WFA may block error-prone DSB repair and sensitize breast cancer cells to killing by DSB-inducing agents. We will determine the role of FANCA in breast cancer development; delineate the molecular mechanisms how FANCA contributes to breast tumorigenesis and cancer development; and determine how WFA targets FANCA, blocks SSA repair, and sensitizes breast cancer cells for effective killing by ionizing irradiation and chemotherapeutic drugs in vitro and in mice. This proposal has significant clinical implication for breast cancer patients, particularly those with TNBC and/or high FANCA expression. It addresses overarching challenges that include the need to identify what drives breast cancer growth; determine how to stop it; and to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. We expect to define the role of FANCA in breast tumorigenesis and cancer development, which should ultimately translate into better and more targeted therapies at the bedside. We will establish the significance of FANCA as a unique therapeutic target for breast cancer treatment. We hope that the use of WFA as a therapeutic approach for high FANCA-expression breast cancer patients can come to fruition within the next few years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910393
Entities
People
- Yanbin Zhang
Organizations
- United States Army
- University of Miami