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

Feng Bai, Shiqin Liu, Xiong Liu, Daniel P. Hollern, Alexandria Scott, Chuying Wang, Lihan Zhang, Cheng Fan, Li Fu, Charles M. Perou, Wei Guo Zhu, Xin Hai Pei

Research output: Contribution to journalArticlepeer-review

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 p16INK4A, or separately p18INK4C, 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 p18INK4C- or p16INK4A-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.

Original languageEnglish (US)
Article number10
JournalBreast Cancer Research
Volume23
Issue number1
DOIs
StatePublished - Dec 2021

Keywords

  • BRCA1
  • EMT
  • Mammary tumor
  • PDGFRβ
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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