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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 I NK4C  , 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 I NK4C  - or p16  INK4A  -deficient mice activated Pdgfrβ signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfrβ in  Brca1 -deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfrβ and its downstream target Pkcα 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 PDGFRβ-PKCα signaling is repressed by BRCA1, which establishes PDGFRβ-PKCα signaling as a therapeutic target for  BRCA1 -deficient breast cancers.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13058-021-01387-x.

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