Abstract P3-01-23: Targeting of endocrine therapy-induced estrogen-receptor/HER2-cross-talk in circulating tumor cells from metastatic ER+/HER2- breast cancer: Implications for treatment of ER+/HER2- breast cancer
Authors: Thaler S , Roßwag S , Pantel K , Sleeman JP , Schmidt M , Cotarelo CL 
Published: May 2019

Background: Transient induction of HER2 expression upon inhibition of the estrogen-receptor (ERα) might be an underestimated rescue mechanism that enables ER+/HER2- breast cancer cells to survive and to grow in the presence of endocrine therapies. Besides protecting ER+/HER2- BC cells from endocrine treatment, transient HER2 expression is also considered to save circulating, disseminated and dormant ER+/HER2- BC cells from apoptotic cell death in hostile environments and might therefore be of importance for ER+ BC progression, metastasis formation and recurrence. Thus therapeutic strategies that efficiently target both ERα and HER2 simultaneously might improve treatment of patient with ER+/HER2- BCs.

Methods: Circulating tumor cells (CTCs) were originally isolated from a patient with bilateral ER+/HER2- metastatic BC. These cells have been treated with either the proteasome inhibitor (PI) carfilzomib or fulvestrant alone or with both drugs in combination. The consequences of these drugs upon ERα and HER2 expression were monitored by western blotting or qPCR. Induction of cell death upon treatment was measured by PARP and caspase cleavage or by quantification of SubG1 cells using propidium iodide staining or by the use of colony forming assays.

Results: Fulvestrant treatment of CTCs decreases the amount of ERα but immediately increases HER2 expression whereas carfilzomib markedly inhibits the expression of both ERα and HER2 simultaneously. Combined treatment of CTCs with carfilzomib + fulvestrant cause reduced expression of HER2 and lead to a much stronger decrease of ERα than carfilzomib or fulvestrant alone. Fulvestrant causes no significant reduction of proliferation and no induction of cell death. Conversely the combination of carfilzomib and fulvestrant causes a significant induction of apoptotic cell death and a massive reduction of colonies in colony forming assays.

Conclusion: These findings suggest that rapid and transient up-regulation of HER2 expression following endocrine treatment might be an important so far underestimated adaptive mechanism which enables ER+/HER2- BC cells to sustain proliferation in the presence of ERα-inhibitory drugs and to stay alive during the metastatic process. Furthermore these data also lead to the assumption that PIs such as carfilzomib in combination with ERα degraders could be a potential therapeutic strategy for efficient targeting of metastatic ER+/HER2- BC cells.

Citation Format: Thaler S, Roßwag S, Pantel K, Sleeman JP, Schmidt M, Cotarelo CL. Targeting of endocrine therapy-induced estrogen-receptor/HER2-cross-talk in circulating tumor cells from metastatic ER+/HER2- breast cancer: Implications for treatment of ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-23.