Abstract P6-12-14: Proteasome inhibitors prevent bi-directional HER2/estrogen-receptor cross-talk leading to cell death in endocrine and lapatinib-resistant HER2+/ER+ breast cancer cells
Authors: Thaler S , Schmidt M , Thiede G , Schad A , Sleeman JP 
Published: March 2017

Background:Aberrant signaling through HER2 and other members of the HER family has been identified as mediator of endocrine resistance in estrogen receptor alpha (ERα) positive breast cancer. On the other hand, ERα co-expression has been shown to attenuate the efficiency of anti-HER2 targeted therapies. These findings indicate that HER2 and ERα synergize to allow breast cancer cells to escape from both anti-ERα and anti-HER2-targeted therapies. Rationally designed clinical trials that combine endocrine therapy with anti-HER2 agents to interfere with HER2/ERα cross-talk have been conducted. However, the outcome of these trials suggests that novel therapeutic approaches are needed to further improve inhibition of HER2 and other HER family members in conjunction with a more efficient ERα blockade. We examined the ability of proteasome inhibitors (PIs) to disrupt HER2/ERα cross-talk in HER2+/ER+ breast cancer (BC) cells. Furthermore we investigated the potential of PIs to suppress the activity of a constitutively active HER2 variant resistant to trastuzumab and lapatinib.

Methode: HER2+/ER+ BC cells and fulvestrant resistant ER+ BC cells that overexpress a constitutively active HER2 variant resistant to trastuzumab and lapatinib have been treated with the PIs carfilzomib and bortezomib. The potential of these PIs to suppress ERα expression, to block HER2 activation and to inhibit the HER2 downstream pathways PI3K/Akt and Ras/MAPK was monitored by western blotting. Induction of cell death upon PI treatment was measured by quantification of SubG1 cells using propidium iodide staining or the use of colony formation assays.

Results: Carfilzomib and bortezomib markedly inhibit bi-directional HER2/ERα signaling pathways in HER2/ER+ BC cells. Both PIs suppress ERα expression, inhibit HER2 activity and subsequently suppress the HER2 downstream pathways PI3K/Akt and Ras/MAPK that are major executors for endocrine resistance. Furthermore we observed that both PIs stabilize the HER2 specific tyrosine phosphatase BDP1 (PTPN18), thereby suppressing the activity of even a constitutive active HER2 variant that cause resistance to trastuzumab and lapatinib. Based on these findings we hypothesize that PIs inhibits ERα and HER2 activity through different mechanisms as currently used therapeutic regiments.

Conclusion: These findings demonstrate that PIs disrupt the cross-talk between HER2 and ERα signaling pathways and therefore might have the potential to expand treatment opportunities for HER2+/ER+ and possibly also for other groups of BC patients.

Citation Format: Thaler S, Schmidt M, Thiede G, Schad A, Sleeman JP. Proteasome inhibitors prevent bi-directional HER2/estrogen-receptor cross-talk leading to cell death in endocrine and lapatinib-resistant HER2+/ER+ breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-14.