TWIST1-mediated transcriptional activation of PDGFR beta in breast cancer stem cells promotes tumorigenesis and metastasis

Triple-negative breast cancer (TNBC) patients often exhibit poor prognosis and breast cancer relapse due to metastasis. This results in secondary tumor generation at distant-unrelated organs that account for the majority of breast cancer-related deaths. Although breast cancer stem cells (CSCs) have been attributed to metastasis, a mechanistic understanding is essential for developing therapeutic interventions to combat breast cancer relapse. Breast CSCs are generated due to Epithelial-to-mesenchymal transition (EMT), regulated by transcription factors (EMT-TF) that are implicated in tumorigenesis and metastasis. However, the underlying mechanisms mediating these processes remain elusive. In the present study, we have reported that TWIST1, an EMT-TF, exhibits positive transcriptional regulation on PDGFR beta promoter, thus identifying PDGFR beta as one of the downstream targets of EMT regulation in breast CSCs. Breast cancer cells overexpressing PDGFR beta exhibited a significant increase in physiological and molecular properties comparable to that of breast CSCs, while molecular silencing of PDGFR beta in breast CSCs perturbed these phenomena. Mechanistically, PDGFR beta overexpression induced the activation of FAK and Src leading to cell migration and invasion. Orthotopic xenograft transplantation of stable breast cancer cells and CSCs with PDGFR beta overexpression in nude mice led to a significant increase in tumorigenesis, and metastasis to lung and liver as depicted by the significant increase in human gene-specific PDGFR beta and CD44 expression, and colocalization along with an expression of human-specific AM sequences which were perturbed with stable silencing of PDGFR beta in breast CSCs. Thus, PDGFR beta plays a crucial role in inducing breast cancer tumorigenesis and metastasis that can be a plausible therapeutic target to treat TNBC patients.

Automated summary

The study demonstrates the crucial role of PDGFR beta in regulating EMT in breast CSCs, leading to increased physiological and molecular properties in breast cancer cells and CSCs with PDGFR beta overexpression. Mechanistically, PDGFR beta overexpression induces FAK and Src activation, promoting cell migration and invasion. Stable silencing of PDGFR beta disrupts these biological phenomena and could be a potential therapeutic target for treating TNBC patients.