Tags

Type your tag names separated by a space and hit enter

Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells.
Clin Cancer Res. 2004 Jun 01; 10(11):3621-8.CC

Abstract

PURPOSE

Approximately two-thirds of breast cancer patients respond to endocrine therapy, and this population of patients is estrogen receptor (ER) positive. However, a significant proportion of patients do not respond to hormone therapy. ER hormone responsiveness is widely believed to be influenced by enhanced cross-talk of ER with overexpressed human epidermal growth factor receptor 2 (HER2), and a subgroup of ER-positive tumors coexpress high HER2.

EXPERIMENTAL DESIGN

Breast cancer cells with or without HER2 overexpression were analyzed for ER status, subcellular localization, and interactions with HER2 signaling components by biochemical and immunological methods. Experiments explored the regulatory interactions between the HER2 and ER pathways and the sensitivity of breast cancer cells to tamoxifen.

RESULTS

Stable or transient or natural HER2 overexpression in ER-positive breast cancer cells promoted the nucleus-to-cytoplasm relocalization of ER, enhanced interactions of ER with HER2, inhibited ER transactivation function, and induced resistance to tamoxifen-mediated growth inhibition of breast cancer cells. In addition, HER2 up-regulation resulted in ER interaction with Sos, a component of Ras signaling, and hyperstimulation of the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). Conversely, down-regulation of HER2 by the anti-HER2 monoclonal antibody Herceptin led to suppression of ERK1/2 stimulation, restoration of ER to the nucleus, and potentiation of the growth-inhibitory action of tamoxifen.

CONCLUSION

The results presented here show for the first time that ER redistribution to the cytoplasm and its interaction with HER2 are important downstream effects of HER2 overexpression, that ERK1/2 is important for ER cytoplasmic localization, and that subcellular localization of ER may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen.

Authors+Show Affiliations

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15173068

Citation

Yang, Zhibo, et al. "Human Epidermal Growth Factor Receptor 2 Status Modulates Subcellular Localization of and Interaction With Estrogen Receptor Alpha in Breast Cancer Cells." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 10, no. 11, 2004, pp. 3621-8.
Yang Z, Barnes CJ, Kumar R. Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells. Clin Cancer Res. 2004;10(11):3621-8.
Yang, Z., Barnes, C. J., & Kumar, R. (2004). Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 10(11), 3621-8.
Yang Z, Barnes CJ, Kumar R. Human Epidermal Growth Factor Receptor 2 Status Modulates Subcellular Localization of and Interaction With Estrogen Receptor Alpha in Breast Cancer Cells. Clin Cancer Res. 2004 Jun 1;10(11):3621-8. PubMed PMID: 15173068.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human epidermal growth factor receptor 2 status modulates subcellular localization of and interaction with estrogen receptor alpha in breast cancer cells. AU - Yang,Zhibo, AU - Barnes,Christopher J, AU - Kumar,Rakesh, PY - 2004/6/3/pubmed PY - 2004/12/28/medline PY - 2004/6/3/entrez SP - 3621 EP - 8 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 10 IS - 11 N2 - PURPOSE: Approximately two-thirds of breast cancer patients respond to endocrine therapy, and this population of patients is estrogen receptor (ER) positive. However, a significant proportion of patients do not respond to hormone therapy. ER hormone responsiveness is widely believed to be influenced by enhanced cross-talk of ER with overexpressed human epidermal growth factor receptor 2 (HER2), and a subgroup of ER-positive tumors coexpress high HER2. EXPERIMENTAL DESIGN: Breast cancer cells with or without HER2 overexpression were analyzed for ER status, subcellular localization, and interactions with HER2 signaling components by biochemical and immunological methods. Experiments explored the regulatory interactions between the HER2 and ER pathways and the sensitivity of breast cancer cells to tamoxifen. RESULTS: Stable or transient or natural HER2 overexpression in ER-positive breast cancer cells promoted the nucleus-to-cytoplasm relocalization of ER, enhanced interactions of ER with HER2, inhibited ER transactivation function, and induced resistance to tamoxifen-mediated growth inhibition of breast cancer cells. In addition, HER2 up-regulation resulted in ER interaction with Sos, a component of Ras signaling, and hyperstimulation of the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2). Conversely, down-regulation of HER2 by the anti-HER2 monoclonal antibody Herceptin led to suppression of ERK1/2 stimulation, restoration of ER to the nucleus, and potentiation of the growth-inhibitory action of tamoxifen. CONCLUSION: The results presented here show for the first time that ER redistribution to the cytoplasm and its interaction with HER2 are important downstream effects of HER2 overexpression, that ERK1/2 is important for ER cytoplasmic localization, and that subcellular localization of ER may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/15173068/Human_epidermal_growth_factor_receptor_2_status_modulates_subcellular_localization_of_and_interaction_with_estrogen_receptor_alpha_in_breast_cancer_cells_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15173068 DB - PRIME DP - Unbound Medicine ER -