HER4 expression in estrogen receptor-positive breast cancer is associated with decreased sensitivity to tamoxifen treatment and reduced overall survival of postmenopausal women.

BACKGROUND: The sensitivity of estrogen receptor-positive breast cancers to tamoxifen treatment varies considerably, and the molecular mechanisms affecting the response rates are manifold. The human epidermal growth factor receptor-related receptor HER2 is known to trigger intracellular signaling cascades that modulate the activity of coregulators of the estrogen receptor which, in turn, reduces the cell sensitivity to tamoxifen treatment. However, the impact of HER2-related receptor tyrosine kinases HER1, HER3, and, in particular, HER4 on endocrine treatment is largely unknown. METHODS: Here, we retrospectively evaluated the importance of HER4 expression on the outcome of tamoxifen- and aromatase inhibitor-treated estrogen receptor-positive breast cancer patients (n = 258). In addition, we experimentally analyzed the efficiency of tamoxifen treatment as a function of HER4 co-expression in vitro. RESULTS: We found a significantly improved survival in tamoxifen-treated postmenopausal breast cancer patients in the absence of HER4 compared with those with pronounced HER4 expression. In accordance with this finding, the sensitivity to tamoxifen treatment of estrogen and HER4 receptor-positive ZR-75-1 breast cancer cells can be significantly enhanced by HER4 knockdown. CONCLUSION: We suggest an HER4/estrogen receptor interaction that impedes tamoxifen binding to the estrogen receptor and reduces treatment efficiency. Whether the sensitivity to tamoxifen treatment can be enhanced by anti-HER4 targeting needs to be prospectively evaluated.

Nuclear factor erythroid 2-related factor 2 modulates HER4 receptor in ovarian cancer cells to influence their sensitivity to tyrosine kinase inhibitors.

Aim: Nuclear factor erythroid 2-related factor 2 (NRF2) is a key component in the cell's response to oxidative and electrophilic stress and is a transcription factor regulating the expression of a collection of anti-oxidative and cytoprotective genes. Human epidermal growth factor receptor 4 (HER4/erbB4) regulates growth and differentiation in many cancer types. Here, NRF2 and HER4 receptor interactions were investigated in a panel of ovarian cancer cell lines. Methods: Pharmacological [tert-butylhydroquinone (tBHQ) and retinoid/rexinoid, bexarotene] and genetic [small interfering RNA (siRNA)] manipulations were used to activate or inhibit NRF2 function in the cell line panel (PE01, OVCAR3, SKOV3). Activity of the HER-targeted tyrosine kinase inhibitors, erlotinib (ERL) and lapatinib (LAP), was evaluated after NRF2 activation. Results: While tBHQ increased the levels of both phosphorylated-NRF2 (pNRF2) and HER4 in PE01, OVCAR3 and SKOV3 cells, bexatorene and NRF2-target siRNA treatment decreased pNRF2 and total HER4 levels. The tBHQ-dependent pharmacological activation of NRF2 attenuated the therapeutic effectiveness of ERL and LAP. Analyses of gene expression data from a HER4 driven reporter system and in vitro or in vivo cancer models, support NRF2 regulation of HER4 expression. Conclusions: These results support the presence of signaling interaction between the NRF2 and HER4 receptor pathways and suggest that intervention modulating this cross-talk could have anticancer therapeutic value.