Abstract
BackgroundBasal-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.MethodsMost 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.ResultsHeterozygous 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.ConclusionsOur 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.
Highlights
Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies
Taking advantage of the majority of p18−/−;Brca1+/− tumors expressing a high level of Pdgfrβ and a few of these tumors expressing a low level of Pdgfrβ, we performed Single sample gene set enrichment analysis (ssGSEA) and found that the lowest Pdgfrβ samples had lower Pdgf signaling as expected (Fig. 1d, Additional file 2A)
Pdgfrβ mRNA levels in p18−/−;Brca1+/− mammary tumors strongly correlated with epithelial-to-mesenchymal transition (EMT) and stem cell signatures (Fig. 1e, f, and Additional file 2B, C, D), in agreement with the data derived from IHC and published elsewhere [31, 59]
Summary
Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. Most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. The heterogeneity of breast cancer is marked by pathologically distinct tumor types that differ in their responsiveness to treatment. More than half of BLBCs are associated with functional loss of BRCA1, caused by germline or somatic mutation or by promoter hypermethylation [19,20,21,22]. BRCA1 is a tumor suppressor that functions in DNA damage repair. The majority of BRCA1-deficient cancer patients respond to DNA-damaging agents such as cisplatin and poly (ADPribose) polymerase (PARP) inhibitors, tumor recurrence and resistance, likely driven by TICs, combine to decrease the 5-year survival of such patients [23, 24]. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed
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