Authors' Affiliations: Cancer Research and Immunology Programs, Garvan Institute of Medical Research; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales; and Department of Anatomical Pathology, SydPath, St Vincent's Hospital, Darlinghurst; Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital; Central Clinical School, University of Sydney; and Department of Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown; Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Kogarah; School of Medical Sciences, University of New South Wales, Kensington; School of Medicine, University of Western Sydney, Campbelltown; and Department of Tissue Pathology, Institute of Clinical Pathology and Medical Research, Westmead, NSW; and Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia; and Experimental Diagnostic Imaging, UT MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2011 Jun 1; 71(11):4002-4014.
Hedgehog (Hh) signaling plays an important role in several malignancies but its clinical significance in breast cancer is unclear. In a cohort of 279 patients with invasive ductal carcinoma of the breast, expression of Hh ligand was significantly associated with increased risk of metastasis, breast cancer-specific death, and a basal-like phenotype. A paracrine signature, encompassing high epithelial Hh ligand and high stromal Gli1, was an independent predictor for overall survival in multivariate analysis. In 2 independent histological progression series (n = 301), Hh expression increased with atypia. Hh ligand overexpression in a mouse model of basal breast cancer increased growth, induced a poorly differentiated phenotype, accelerated metastasis, and reduced survival. A stromal requirement for these effects was supported by the lack of similar Hh-mediated changes in vitro, and by stromal-specific expression of Hh target genes in vivo. Furthermore, inhibition of Hh ligand with a monoclonal antibody (5E1) inhibited tumor growth and metastasis. These data suggest that epithelial-stromal Hh signaling, driven by ligand expression in carcinoma cells, promotes breast cancer growth and metastasis. Blockade of Hh signaling to peritumoral stromal cells may represent a novel therapeutic approach in some basal-like breast cancers. Cancer Res; 71(11); 4002-14. ©2011 AACR.
PMID: 21632555 [PubMed - as supplied by publisher] Source: National Library of Medicine.
