The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive
breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout
variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We
investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen,
abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially
affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased
sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by
NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen
and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the
corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth
in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but
human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7
in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor
growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients
with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced
event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib
treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is
associated with unfavorable outcomes in abemaciclib-treated patients.