Dual Targeting of Estrogen Receptor α and Estrogen-related Receptor α: a Novel Endocrine Therapy for Endometrial Cancer

Background: Endometrial cancer (EC) is a hormone dependent carcinoma that may involve complex molecular mechanisms. Endocrine therapy by blocking the estrogen and estrogen receptor α (ERα) has been effective in breast cancer, while it is still controversial in EC. Recently, estrogen-related receptor α (ERRα) was proven to be another endocrine therapy target.

Methods: The anti-tumor effect of selective estrogen receptor modulators (SERMs) and XCT790 (XCT) used alone or in combination were evaluated in both of ERα-positive (ERα+) and ERα-negative (ERα-) EC cells. ERα and ERRα mRNA were tested by qPCR, while the protein was detected by Western blot. The proliferation was tested by MTS and cell cycle, apoptosis rate were analyzed by flow cytometry.

Results: A relatively high dose (10 μM) of tamoxifen (TAM) suppressed the expression of ERα and ERRα in two types of EC cells. However, 10 μM raloxifene (RAL) exhibited no effect on ERα and ERRα, while 10 μM XCT down regulated ERRα specifically, but not ERα in all EC cells. When dual targeting on ERα and ERRα by combining TAM with XCT, the proliferation inhibitory effect and apoptosis reached the strongest in all EC cells (<0.05). Moreover, the inhibitory effect of proliferation was attributed significantly to the G0/G1 arrest (<0.05). Interestingly, the apoptosis induced by combining TAM with XCT were obviously higher in ERα+ EC cells than ERα- EC cells (<0.05).

Conclusion: Taken together, the results indicate that dual targeting on ERα and ERRα represents a better anti-tumor effect, which provides a novel endocrine based therapy strategy for EC.