Lapatinib Restores Hormone Sensitivity with Differential Effects on Estrogen Receptor Signaling in Cell Models of Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer with Acquired Endocrine Resistance

Abstract

Purpose: Acquired endocrine resistance in estrogen receptor (ER)α+/human epidermal growth factor receptor 2–negative (HER2−) breast cancer has been associated with modest adaptive increases in HER2, although exactly how aberrant HER2 signaling affects the ERα pathway is poorly understood. We investigated (a) whether the epidermal growth factor receptor/HER2 inhibitor lapatinib could restore endocrine responsiveness in cell models of acquired endocrine resistance with modest increases in HER2, and (b) the nature of ERα-HER2 cross-talk in this process. Methods: Combination growth studies, ERα transcription, immunoblot, and gene expression assays were conducted in two models of acquired resistance to (a) estrogen deprivation (long-term estrogen-deprived cells) and (b) tamoxifen (long-term tamoxifen-treated cells), and in hormone sensitive controls. Changes in ERα, PgR, and HER2 were assessed in samples from patients treated with tamoxifen. Results: Both cell models of acquired endocrine resistance showed modest adaptive upregulation in HER2, and lapatinib restored endocrine sensitivity in both. The effect of lapatinib on ERα signaling varied markedly depending on the nature of the HER2/ERα cross-talk. In long-term estrogen-deprived cells characterized by enhanced ERα function, lapatinib suppressed ERα genomic activity (as measured by pERSer118, ERα transcriptional activity, and PGR gene expression). In contrast, in long-term tamoxifen-treated cells with reduced ERα activation, lapatinib reactivated ERα genomic function. Twenty percent of tamoxifen-resistant patients relapsed with modest increases in HER2 and either suppressed or enhanced ERα/PgR expression. Conclusions: Aberrant GFR signaling can augment or suppress ERα function. Regardless, interrupting the HER2/ERα cross-talk with lapatinib can restore endocrine sensitivity and should be investigated as a therapeutic strategy in combination with endocrine therapy in ERα+/HER2− patients with acquired endocrine resistance. Clin Cancer Res; 16(5); 1486–97