PDGFRβ is an essential therapeutic target for BRCA1-deficient mammary tumors
| Autor: | Xin Hai Pei, Chuying Wang, Xiong Liu, Cheng Fan, Feng Bai, Wei Guo Zhu, Daniel P. Hollern, Charles M. Perou, Li Fu, Shiqin Liu, Li-Han Zhang, Alexandria Scott |
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| Rok vydání: | 2021 |
| Předmět: |
endocrine system diseases
medicine.medical_treatment PDGFRβ Gene Expression Tumor initiation medicine.disease_cause Targeted therapy Mice 0302 clinical medicine Surgical oncology Medicine Molecular Targeted Therapy skin and connective tissue diseases Mice Knockout 0303 health sciences Mammary tumor BRCA1 Protein EMT Disease Management lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunohistochemistry Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Female Disease Susceptibility Protein Binding Signal Transduction Research Article Heterozygote Programmed cell death Epithelial-Mesenchymal Transition Breast Neoplasms lcsh:RC254-282 Receptor Platelet-Derived Growth Factor beta 03 medical and health sciences Breast cancer Cell Line Tumor Biomarkers Tumor Animals Cyclin-Dependent Kinase Inhibitor p18 Humans Cyclin-Dependent Kinase Inhibitor p16 Germ-Line Mutation 030304 developmental biology business.industry BRCA1 medicine.disease Disease Models Animal Cancer cell Cancer research business Carcinogenesis |
| Zdroj: | Breast Cancer Research, Vol 23, Iss 1, Pp 1-17 (2021) Breast Cancer Research : BCR |
| ISSN: | 1465-542X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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