Hedgehog Overexpression Is Associated with Stromal Interactions and Predicts for Poor Outcome in Breast Cancer

Sandra A O’toole ,Daniel Christ,Robert L Sutherland,D Neil Watkins,Duncan Mcleod,Elizabeth A Musgrove,Alexander Swarbrick,Akira Nguyen,Luciano G Martelotto,Radhika Nair,Gregory E Hannigan,Christopher J Ormandy,Ewan K.A Millar,Andrea Mcfarland,Robert F Shearer,Duc Vu,Catriona M Mcneil,Brian A Rabinovich ,Peter R Schofield ,Caroline Cooper ,Min Qiu ,Dorothy A Machalek

doi:10.1158/0008-5472.can-10-3738

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.

Highlights

Kaplan–Meier survival analysis showed that those patients had a poorer outcome in terms of breast cancer metastasis (P 1⁄4 0.0004, HR 1.95, 95% CI 1.2–3.1) and breast cancer–specific death (P 1⁄4 0.002, HR 2.3, 95% CI 1.3–4.0, Fig. 1B)
We report that the expression of Hh ligand in the epithelial cells of breast cancer is associated with increased risk of metastasis, breast cancer– specific death, and a more proliferative, aggressive, basal-like phenotype and that Hh ligand expression increases during progression of premalignant breast epithelial lesions
Our data support a paracrine mode of canonical Hh signaling in breast cancer, we cannot exclude a cellautonomous role for Hh signaling in a small subset of tumors, or within a small population of tumor cells within a given tumor

Summary

Introduction

The decrease in deaths from breast cancer over the last 2 decades reflects improvements in early detection, and the success of targeted therapies such as tamoxifen in hormone. Recent data show that therapeutic targeting of the HER2 receptor is making an impact in breast cancer mortality [2]. There is a shortage of targetable signaling pathways in basallike breast cancer. Several studies have suggested a role for hedgehog (Hh) signaling in breast cancer [4,5,6]. This pathway is a highly conserved developmental signaling system essential for epithelial to mesenchymal signaling in development [7]. Deregulation of Hh signaling has been implicated in the pathogenesis of carcinoma, in part through the promotion of epithelial–stromal interactions [8,9,10]

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