Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer

Ali Naderi, Michelle Meyer, Dennis H. Dowhan

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)283-296
Number of pages14
JournalNeoplasia
Volume14
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

Fingerprint

Estrogen Receptors
Breast Neoplasms
erbB-2 Genes
Genes
Cell Line
Co-Repressor Proteins
Extracellular Signal-Regulated MAP Kinases
Androgen Receptors
Cell Survival
Transcription Factors
Down-Regulation
Steroids
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research

Cite this

Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer. / Naderi, Ali; Meyer, Michelle; Dowhan, Dennis H.

In: Neoplasia, Vol. 14, No. 4, 04.2012, p. 283-296.

Research output: Contribution to journalArticle

Naderi, Ali ; Meyer, Michelle ; Dowhan, Dennis H. / Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer. In: Neoplasia. 2012 ; Vol. 14, No. 4. pp. 283-296.
@article{166f8b8eeb364c71b058ff87c45baba9,
title = "Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer",
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.",
author = "Ali Naderi and Michelle Meyer and Dowhan, {Dennis H.}",
year = "2012",
month = "4",
doi = "10.1593/neo.12294",
language = "English (US)",
volume = "14",
pages = "283--296",
journal = "Neoplasia (United States)",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Cross-regulation between FOXA1 and ErbB2 signaling in estrogen receptor-negative breast cancer

AU - Naderi, Ali

AU - Meyer, Michelle

AU - Dowhan, Dennis H.

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84860607999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860607999&partnerID=8YFLogxK

U2 - 10.1593/neo.12294

DO - 10.1593/neo.12294

M3 - Article

C2 - 22577344

AN - SCOPUS:84860607999

VL - 14

SP - 283

EP - 296

JO - Neoplasia (United States)

JF - Neoplasia (United States)

SN - 1522-8002

IS - 4

ER -