PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors

Background: Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed. Methods: Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16(INK4A), or separately p18(INK4C), to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers. Results: Heterozygous germline or epithelium-specific deletion of Brca1 in p18(INK4C)- or p16(INK4A)-deficient mice activated Pdgfr beta signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfr beta in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfr beta and its downstream target Pkc alpha suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells. Conclusions: Our work offers the first genetic and biochemical evidence that PDGFR beta-PKC alpha signaling is repressed by BRCA1, which establishes PDGFR beta-PKC alpha signaling as a therapeutic target for BRCA1-deficient breast cancers.