PDGFR? is an essential therapeutic target for BRCA1-deficient mammary tumors.

ABSTRACT:

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? signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfr? 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? and its downstream target Pkc? 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?-PKC? signaling is repressed by BRCA1, which establishes PDGFR?-PKC? signaling as a therapeutic target for BRCA1-deficient breast cancers.

SUBMITTER: Bai F 

PROVIDER: S-EPMC7819225 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature