SCIENCE@home

Cross-regulation between FOXA 1 and ErbB 2 Signaling in Estrogen Receptor – Negative Breast Cancer 1 , 2

A. Naderi,Michelle Meyer,D. Dowhan

Published 2014 in Unknown venue

ABSTRACT

Molecular apocrine is a subtype of estrogen receptor–negative (ER−) breast cancer, which is characterized by a steroid-response gene signature that includes androgen receptor, FOXA1, and a high frequency of ErbB2 overexpression. In this study, we demonstrate that there is a strong association between the overexpression of FOXA1 and ErbB2 in ER− breast tumors. This has led us to identify a cross-regulation network between FOXA1 and ErbB2 signaling in ER− breast cancer. We present two mechanisms to explain the association between FOXA1 and ErbB2 overexpression in molecular apocrine cells. In one process, ErbB2 signaling genes CREB1 and c-Fos regulate FOXA1 transcription, and in another process, AP2α regulates the expression of both FOXA1 and ErbB2. Moreover, we demonstrate that FOXA1, in turn, regulates the transcription of ErbB2 signaling genes. This includes a core gene signature that is shared across two molecular apocrine cell lines. Importantly, the most upregulated (RELB) and downregulated (PAK1) genes in this signature are direct FOXA1 targets. Our data suggest that FOXA1 acts as a dual-function transcription factor and the repressive function of FOXA1 on RELB can be explained by the recruitment of its binding partner corepressor TLE3. It is notable that a group of FOXA1-regulated genes vary across molecular apocrine cell lines leading to the differences in the functional effects of FOXA1 on extracellular signal–regulated kinase phosphorylation and cell viability between these lines. This study demonstrates that there is a cross-regulation network between FOXA1 and ErbB2 signaling that connects FOXA1 to some of the key signaling pathways in ER− breast cancer. Neoplasia (2012) 14, 283–296 Introduction Estrogen receptor–negative (ER−) breast cancer is a heterogeneous disease that constitutes around 30% of all cases [1]. To develop effective targeted therapies for ER− breast cancer, there is need to better understand the biology of this disease. ER− breast cancer can be divided into molecular apocrine and basal subtypes based on expression microarray profiling [2]. Molecular apocrine subtype is characterized by a steroid-response gene signature that includes androgen receptor (AR), FOXA1, TFF3, and a high frequency of ErbB2 overexpression (ErbB2+) [2–4]. Recent studies have shown that AR expression is observed in approximately 50% of ER− breast tumors and more than 50% of these cases also have ErbB2 overexpression [5–7]. There is a growing body of evidence to support a significant role for the AR and ErbB2 signaling pathways in molecular apocrine breast cancer. Notably, there is a functional cross talk between the AR and ErbB2 signaling in molecular apocrine cells, which modulates cell proliferation and expression of steroid-response genes [8]. Moreover, we have recently identified a positive feedback loop between the AR signaling and extracellular signal–regulated kinase (ERK) pathways in molecular apocrine breast cancer [9]. In this feedback loop, AR regulates ERK phosphorylation through the mediation of ErbB2 and, in turn, ERK-CREB1 signaling regulates the transcription of AR inmolecular apocrine cells [9]. Furthermore, it has been shown that Address all correspondence to: Ali Naderi, MD, Level 4, R Wing, Bldg 1, Princess AlexandraHospital, Ipswich Rd, Brisbane,Qld 4102, Australia. E-mail: a.naderi@uq.edu.au This study is funded by grants from Princess Alexandra Hospital Private Practice Trust Fund, Cancer Collaborative Group, and Cancer Council Queensland. This article refers to supplementary materials, which are designated by Table W1 and Figure W1, and are available online at www.neoplasia.com. Received 2 February 2012; Revised 11 March 2012; Accepted 13 March 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.12294 www.neoplasia.com Volume 14 Number 4 April 2012 pp. 283–296 283

PUBLICATION RECORD

  • Publication year

    2014

  • Venue

    Unknown venue

  • Publication date

    Unknown publication date

  • Fields of study

    Not labeled

  • Identifiers

    No identifiers available.

  • External record

    Open on Semantic Scholar

  • Source metadata

    Semantic Scholar

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-58 of 58 references · Page 1 of 1

CITED BY