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

Abstract

BackgroundThe 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.MethodsHere, 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.ResultsWe 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.ConclusionWe 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.

Target HER four in breast cancer?

“…Years ago, HER4 (i.e., 4ICD) has already been shown to co-activate estrogen receptor related transcription and thereby to promote tumor cell growth and proliferation [15, 29]. Based on this finding and other evidences we recently demonstrated an improved outcome of ER positive and tamoxifen treated postmenopausal breast cancer patients in the absence of HER4 expression [30]. In contrast, we found no impact of HER4 in patients treated with aromatase inhibitors which indicated some kind of 4ICD/ER/tamoxifen interaction.…”

“…Overall, we revealed strong evidence that HER4 (or more specifically 4ICD) impedes the tamoxifen-estrogen receptor interaction and thereby attenuates the tamoxifen treatment efficiency. Accordingly, we provided a model of action of the molecular troika consisting of 4ICD/ER/tamoxifen that explains an improved response to tamoxifen treatment in the absence and an impaired response in the presence of HER4 [30].…”

Targeting the Human Epidermal Growth Factor Receptor Family in Breast Cancer beyond HER2

“…An advantageous impact of HER4 expression in breast cancer has been mechanistically attributed to ligand-dependent (i.e., HRG) receptor activation and the subsequent triggering of differentiation pathways that in turn antagonize oncogenic cellular features generated by other coexpressed HER receptor family members, above all HER2. It is assumed that via HER4-mediated signaling an interaction with the ER pathway occurs, leading to an improved outcome of ER-positive and tamoxifen-treated postmenopausal breast cancer patients in the absence of HER4 expression [41]. HER4 may also play a key role in the survival of HER2-positive cancer cells after they de-velop resistance to the anti-HER2 inhibitors lapatinib and trastuzumab [42].…”

Identification of potential gene associated with berberine in overcoming tamoxifen resistance by functional network analysis

“…Genetic alterations in ERBB4, namely, rs13423759, not only enhance breast cancer risk but are also associated with the increased metastasis in patients with breast cancer (Mansouri Bidkani et al, 2018). The interaction between HER4 and ER hinders the binding of tamoxifen to the ER, thereby inducing tamoxifen resistance (Wege et al, 2018). Moreover, the same author demonstrated that the overexpression of HER4 reduces the overall survival of postmenopausal women.…”