Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity

Roshan Sriram,Bruce McKay,William J Muller,Simon J Conway,Benjamin Pryce,Luc A Sabourin,Lilia Antonova,Vivian Lo,Alan J Mears,Manijeh Daneshmand

doi:10.1186/s13058-014-0513-8

Abstract

IntroductionPeriostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer.MethodsUsing transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis.ResultsAlthough Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn-null animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn-null environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15).ConclusionsTogether our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0513-8) contains supplementary material, which is available to authorized users.

Highlights

Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis
Prior to the introduction of the Postn-null allele into mammary tumor virus (MMTV)-NeuNDL mice, we assessed Postn expression and whether Postn ablation was compatible with normal mammary gland development
In contrast to what has been observed in a C57/Bl6 background [14], the viable Postn-null pups displayed a mild growth retardation phenotype that became negligible by 9 weeks of age

Summary

Introduction

Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer. The epidermal growth factor receptor (EGFR), or HER/ ErbB family of receptor tyrosine kinases (RTKs), includes four members, EGFR/HER1/ErbB1, HER2/ErbB2/Neu, HER3/ErbB3, and HER4/ErbB4 playing a role in multiple biological processes such as proliferation, differentiation, migration, and apoptosis [1,2,3]. Activation of the intracellular kinase domain, through the phosphorylation of carboxyl-terminal tyrosines on HER/ErbB receptors, HER2 (ErbB-2/Neu) is overexpressed in approximately 30% of primary human breast cancers (reviewed [5,6]). HER2 overexpression leads to an aggressive tumor phenotype as high levels of HER2 expression are observed in many invasive human ductal carcinomas, but rarely observed in benign breast disorders.

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