Abstract
AbstractMortality in breast cancer patients ultimately results from the dissemination of breast cancer cells (BCCs) from the primary tumor to distant organs (metastasis). The proliferation of BCCs leads to areas of decreased oxygen availability (intratumoral hypoxia), which drives breast cancer pathogenesis through the activation of hypoxia-inducible factors (HIFs). In this review, we outline emerging HIF-dependent molecular mechanisms that promote the metastatic dissemination of hypoxic BCCs through the lymphatic and circulatory systems. We show that HIFs contribute to key aspects of metastatic progression through the transcriptional activation of target genes in BCCs, lymphatic vessels, blood vessels, and supporting stromal cells within the primary tumor. Finally, we discuss the pharmacological inhibition of HIFs as a novel therapeutic approach to block breast cancer metastasis and improve patient survival.KeywordsBone marrow derived cellsEMTExtracellular matrixExtravasationHIF-1IntravasationLymphangiogenesisLymphatic metastasisMarginationTumor stroma
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