Journal Article

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

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

2021

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animals / Antibodies / Biomarkers, Tumor / Biomedical and Life Sciences / Biomedicine / BRCA1 / BRCA1 protein / BRCA1 Protein - deficiency / BRCA1 Protein - genetics / BRCA1 Protein - metabolism / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - etiology / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer Research / Cell death / Cell Line, Tumor / CRISPR / Cyclin-Dependent Kinase Inhibitor p16 - genetics / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / Cyclin-Dependent Kinase Inhibitor p18 - genetics / Cyclin-Dependent Kinase Inhibitor p18 - metabolism / Cyclin-dependent kinase inhibitors / Deoxyribonucleic acid / Disease Management / Disease Models, Animal / Disease Susceptibility / DNA / DNA damage / EMT / Epithelial-Mesenchymal Transition - genetics / Epithelium / Female / Fibroblasts / Gene deletion / Gene Expression / Gene Expression Regulation, Neoplastic / Genetic engineering / Germ-Line Mutation / Heterozygote / Histopathology / Humans / Immunohistochemistry / INK4 protein / INK4a protein / Kinases / Laboratories / Mammary tumor / Mesenchyme / Mice / Mice, Knockout / Molecular Targeted Therapy / Oncology / p16 Protein / PDGFRβ / Plasmids / Protein Binding / Protein kinase C / Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors / Receptor, Platelet-Derived Growth Factor beta - metabolism / Research Article / Senescence / Signal Transduction / Surgical Oncology / Targeted therapy / Therapeutic applications / Therapeutic targets / Tumor cells / Tumorigenesis / Tumors