Gain of HIF1 Activity and Loss of miRNA <i>let-7d</i> Promote Breast Cancer Metastasis to the Brain via the PDGF/PDGFR Axis

Abstract Early detection and adjuvant therapies have significantly improved survival of patients with breast cancer over the past three decades. In contrast, management metastatic disease remains unresolved. Brain metastasis is a late complication frequently observed among cancer, whose poor prognosis calls for novel more effective therapies. Here, we report that active hypoxia inducible factor-1 (HIF1) signaling loss miRNA let-7d concur to promote brain in recently established model spontaneous from primary site (4T1-BM2), additionally murine human experimental models (D2A1-BM2 MDA231-BrM2). Active HIF1 upregulated expression platelet-derived growth factor (PDGF) B/A cells, respectively, while either individual silencing HIF1? PDGF-A/B or overexpression suppressed formation tested models. Let-7d activity, indicating regulatory hierarchy system. The clinical relevance identified targets was supported by gene data analyses. Treatment mice nilotinib, kinase inhibitor impinging on PDGF receptor (PDGFR) signaling, prevented metastases 4T1-BM2 reduced mouse These results identify as coordinated events promoting through increased PDGF-A/B. Moreover, they PDGFR inhibition potentially actionable therapeutic strategy metastatis. Significance: findings show promotes via pharmacologic suppresses metastasis, suggesting opportunities.