THE ROLE OF TREFOIL FACTOR 3 IN MEDIATING RESISTANCE TOWARDS HER2-TARGETED DRUGS IN BREAST CANCER

Abstract

The HER2-estrogen receptor crosstalk contributes to therapeutic resistance in HER2+/ER+ breast cancer. TFF3 is a crucial oncogene and mediator of anti-estrogen resistance in breast cancer. Here, the cross-regulation between HER2 and estrogen-responsive TFF3, and the functional role of TFF3 in trastuzumab resistant HER2+/ER+ breast cancer were investigated. We found that HER2 negatively regulates its own signaling through transcriptional repression of TFF3, while trastuzumab inhibition of HER2 increases TFF3 to compensate for loss of HER2 signaling. In trastuzumab resistant HER2+/ER+ breast cancer cells, TFF3 was markedly upregulated with a corresponding decrease in HER signaling. The inhibition of TFF3 decreased the survival and growth advantage of these resistant cells without re-sensitization to trastuzumab, indicating a shift in oncogene addiction from HER2 to TFF3. Furthermore, TFF3 inhibition abrogated the enhanced cancer stem cell-like behavior in these trastuzumab resistant cells. Taken together, TFF3 is a potential biomarker and therapeutic target in trastuzumab resistant HER2+/ER+ breast cancer.