title: Hedgehog overexpression is associated with stromal interactions and predicts for poor outcome in breast cancer.
abstract: 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.
authors.affiliation: Cancer Research, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: O'Toole
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Machalek
authors.forename: Robert F
authors.initials: RF
authors.lastname: Shearer
authors.forename: Ewan K A
authors.initials: EK
authors.lastname: Millar
authors.forename: Radhika
authors.initials: R
authors.lastname: Nair
authors.forename: Peter
authors.initials: P
authors.lastname: Schofield
authors.forename: Duncan
authors.initials: D
authors.lastname: McLeod
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Cooper
authors.forename: Catriona M
authors.initials: CM
authors.lastname: McNeil
authors.forename: Andrea
authors.initials: A
authors.lastname: McFarland
authors.forename: Akira
authors.initials: A
authors.lastname: Nguyen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ormandy
authors.forename: Min Ru
authors.initials: MR
authors.lastname: Qiu
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.forename: Luciano G
authors.initials: LG
authors.lastname: Martelotto
authors.forename: Duc
authors.initials: D
authors.lastname: Vu
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Hannigan
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: Daniel
authors.initials: D
authors.lastname: Christ
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.forename: Alexander
authors.initials: A
authors.lastname: Swarbrick
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D053823:Hedgehog Proteins / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011379:Prognosis; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D053823:Hedgehog Proteins