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Background:Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and a potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway in regulating TNBC-dependent angiogenesis was investigated.Methods:Expression and regulation of the Hh pathway transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on the endothelial compartment and on TNBC-initiated angiogenesis. To evaluate the translational relevance of our findings, the combination of paclitaxel with the Smo inhibitor NVP-LDE225 was tested in TNBC xenografted mice.Results:Tissue microarray analysis on 200 TNBC patients showed GLI1 overexpression paired with vascular endothelial growth factor receptor 2 (VEGFR2) expression. In vitro, Hh pathway promotes TNBC progression in an autocrine manner, regulating the VEGF/VEGFR2 loop on cancer cell surface, and in a paracrine manner, orchestrating tumour vascularisation. These effects were counteracted by Smo pharmacological inhibition. In TNBC xenografted mice, scheduling NVP-LDE225 rather than bevacizumab provided a better sustained inhibition of TNBC cells proliferation and endothelial cells organisation.Conclusions:This study identifies the Hh pathway as one of the main regulators of tumour angiogenesis in TNBC, thus suggesting Hh inhibition as a potential new anti-angiogenic therapeutic option to be clinically investigated in GLI1 overexpressing TNBC patients. [ABSTRACT FROM AUTHOR]

The existence of a 'metastasis gene signature' that predisposes primary breast cancer cells to metastasize to the lungs has been recently highlighted by gene expression profiling studies. The combination of genes responsible for this process includes genes encoding several metalloproteinases as well as the gene encoding SPARC (secreted protein acidic and rich in cysteine)/osteonectin. SPARC is involved in normal tissue remodeling as it regulates the deposition of extracellular matrix, but also plays a role in neoplastic transformation. Aberrant SPARC expression has been detected both in stromal cells associated with cancer and in cancer cells. The main aim of this study was to investigate whether or not SPARC might be involved in directing metastasis of other types of cancer to the lung. We constructed a tissue microarray containing lung metastases from a variety of primary tumors in different organs and used immunohistochemistry to assess SPARC expression. We found SPARC overexpressed mainly in lung metastases from melanoma. We then assessed the expression of SPARC mRNA and protein in metastatic melanoma from different anatomic sites and in their corresponding primary tumors, and found that it is overexpressed in lung metastases. Our data strongly support the hypothesis that SPARC is involved in directing melanoma metastases specifically to the lung, which underpins its potential as prognostic marker and novel target for specific therapy. [ABSTRACT FROM AUTHOR]