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HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen
University of Örebro, Sweden.
Örebro University Hospital, Sweden.
Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
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2015 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, 1311-1320 p.Article in journal (Refereed) Published
Abstract [en]

The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (Pless than0.0005), PgR-negativity (Pless than0.0005), tumor size greater than20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

Place, publisher, year, edition, pages
SPANDIDOS PUBL LTD , 2015. Vol. 47, no 4, 1311-1320 p.
Keyword [en]
breast cancer; ErbB4; HER4; randomized patients; tamoxifen
National Category
Cancer and Oncology
URN: urn:nbn:se:liu:diva-122207DOI: 10.3892/ijo.2015.3108ISI: 000362058300015PubMedID: 26238412OAI: diva2:864341

Funding Agencies|Nyckelfonden, Orebro University Hospital, Sweden; Lions Cancer Research Foundation, Region Uppsala - Orebro, Sweden; Stockholm Cancer Society, Sweden

Available from: 2015-10-26 Created: 2015-10-23 Last updated: 2015-12-10

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Stål, Olle
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Department of Clinical Pathology and Clinical GeneticsDivision of Clinical SciencesFaculty of Medicine and Health SciencesDepartment of Oncology
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