The ERα coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium

Molecular Cancer

Short Communication

Partha M Das¹  Frank E Jones¹  Jerzy Rokicki¹  Jennifer M Giltnane²  David L Rimm²  Olivia Wansbury³  Beatrice A Howard³ 

[1] Department of Cell and Molecular Biology, Tulane University, 70118, New Orleans, Louisiana, USA;Department of Pathology, Yale University School of Medicine, 06520, New Haven, Connecticut, USA;The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, SW36JB, London, UK;

关键词: Tamoxifen;    Mammary Gland;    Fulvestrant;    Mouse Mammary Gland;    TamR Cell;   

DOI  :  10.1186/1476-4598-9-150

 received in 2009-11-02, accepted in 2010-06-15,  发布年份 2010

来源: Springer

【 摘 要 】

The HER4 intracellular domain (4ICD) is a potent estrogen receptor (ERα) coactivator with activities in breast cancer and the developing mammary gland that appear to overlap with progesterone receptor (PgR). In fact, 4ICD has recently emerged as an important regulator and predictor of tamoxifen response, a role previously thought to be fulfilled by PgR. Here we investigated the possibility that the 4ICD coactivator regulates PgR expression thereby providing a mechanistic explanation for their partially overlapping activities in breast cancer. We show that 4ICD is both sufficient and necessary to potentiate estrogen stimulation of gene expression. Suppression of HER4/4ICD expression in the MCF-7 breast tumor cell line completely eliminated estrogen stimulated expression of PgR. In addition, the HER4/4ICD negative MCF-7 variant, TamR, failed to express PgR in response to estrogen. Reintroduction of wild-type HER4 but not the γ-secretase processing mutant HER4V673I into the TamR cell line restored PgR expression indicating that 4ICD is an essential PgR coactivator in breast tumor cells. These results were substantiated in vivo using two different physiologically relevant experimental systems. In the mouse mammary gland estrogen regulates expression of PgR-A whereas expression of PgR-B is estrogen independent. Consistent with a role for 4ICD in estrogen regulated PgR expression in vivo, PgR-A, but not PgR-B, expression was abolished in HER4-null mouse mammary glands during pregnancy. Coexpression of PgR and 4ICD is also commonly observed in ERα positive breast carcinomas. Using quantitative AQUA IHC technology we found that 4ICD potentiated PgR expression in primary breast tumors and the highest levels of PgR expression required coexpression of ERα and the 4ICD coactivator. In summary, our results provide compelling evidence that 4ICD is a physiologically important ERα coactivator and 4ICD cooperates with ERα to potentiate PgR expression in the normal and malignant breast. We propose that direct coupling of these signaling pathways may have important implications for mammary development, breast carcinogenesis, and patient response to endocrine therapy.

【 授权许可】

Unknown   
© Rokicki et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.