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 (P<0.0005), PgR-negativity (P<0.0005),
tumor size >20 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.