Targeting Posttranslational Modifications in Breast Cancer Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2- targeted therapies. While the newly approved PARP inhibitors (PARPi) such as olaparib and talazoparib provide a glint of hope to the approximately 15-20% of TNBC patients with BRCA1-deficiency, the need for a novel strategy that could benefit the remaining 80-85% BRCA1-proficient TNBC patients is urgent and significant. The goal of this project is to determine the impact of interplay between Krppel-like factor 4 (KLF4) and poly-ADP- ribose polymerase 1 (PARP1) in breast tumor progression and metastasis, and further develop a small molecule inhibitor of KLF4 that synergizes with PARPi for anti-TNBC treatment. This proposal is based on our original discovery that KLF4 acts as a critical signaling node in mediating DNA damage response (DDR)/DNA repair, wherein the Poly-(ADP-ribosyl)ation (PARylation) of KLF4 by PARP1 dictates the chromatin recruitment for KLF4 that, in turn, governs KLF4 transcriptional function with respect to the maintenance of genome stability, tumor progression/metastasis and drug sensitivity in breast cancer. These findings led to our central hypothesis that dysregulation of KLF4 by PARP1 results in genome instability and tumor promotes progression/metastasis, and blockade of KLF4 by newly developed KLF4 inhibitor synergizes PARPi for efficient killing of TNBC cells.
Three specific aims are proposed to elucidate the importance and mechanisms regulating KLF4 by PARP1: (1) To determine the mechanism by which PARP1 regulates KLF4-mediated genome stability and carcinogenesis through orchestrating the recruitment of KLF4 to chromatin; (2) To determine the physiological and clinical relevance of KLF4 PARylation in breast tumor progression/metastasis; and (3) To validate the therapeutic intervention of KLF4 inhibitor in synergizing with olaparib/talazoparib in anti-TNBC treatment using human breast tumor organoid and patient-derived xenografts (PDXs). ! ! !
Results from recent TCGA and pathological studies imply the oncogenic role for KLF4 in breast carcinogenesis, although the underlying molecular mechanisms by which dysregulation of KLF4 contributes to breast tumor initiation, progression and metastasis remain unknown. This proposal will determine the impact of interplay between KLF4 and PARP1 in breast tumor progression and metastasis, and further develop a small molecule inhibitor of KLF4 that synergizes with PARP inhibitors for anti-breast cancer treatment, especially for triple negative type breast cancers. Completion of this project will uncover the mitogenic role of KLF4 in breast cancer development, and could provide a new strategy for breast cancer therapy by synergism PARP1 and KLF4.
