Release of HER2 repression of trefoil factor 3 (TFF3) expression mediates trastuzumab resistance in HER2+/ER+ mammary carcinoma.

Qing-Yun Chong,Arindam Banerjee,Salundi Basappa,Mengyi Zhang,Tao Zhu,Liang Liu,Han-Ming Poh,Ming-Liang You,Lan Ma,Peter E Lobie,Vijay Pandey,Yi-Jun Chen

doi:10.18632/oncotarget.18431

Abstract

HER2+/ER+ breast cancer, a subset of the luminal B subtype, makes up approximately 10% of all breast cancers. The bidirectional crosstalk between HER2 and estrogen receptor (ER) in HER2+/ER+ breast cancer contributes to resistance towards both anti-estrogens and HER2-targeted therapies. TFF3 promotes breast cancer progression and has been implicated in anti-estrogen resistance in breast cancer. Herein, we investigated the cross-regulation between HER2 and estrogen-responsive TFF3, and the role of TFF3 in mediating trastuzumab resistance in HER2+/ER+ breast cancer. TFF3 expression was decreased by HER2 activation, and increased by inhibition of HER2 with trastuzumab in HER2+/ER+ breast cancer cells, partially in an ERα-independent manner. In contrast, the forced expression of TFF3 activated the entire HER family of receptor tyrosine kinases (HER1-4). Hence, HER2 negatively regulates its own signalling through the transcriptional repression of TFF3, while trastuzumab inhibition of HER2 results in increased TFF3 expression to compensate for the loss of HER2 signalling. In HER2+/ER+ breast cancer cells with acquired trastuzumab resistance, TFF3 expression was markedly upregulated and associated with a corresponding decrease in HER signalling. siRNA mediated depletion or small molecule inhibition of TFF3 decreased the survival and growth advantage of the trastuzumab resistant cells without re-sensitization to trastuzumab. Furthermore, TFF3 inhibition abrogated the enhanced cancer stem cell-like behaviour in trastuzumab resistant HER2+/ER+ breast cancer cells. Collectively, TFF3 may function as a potential biomarker and therapeutic target in trastuzumab resistant HER2+/ER+ breast cancer.

Highlights

HER2/neu- and estrogen receptor α-positive (HER2+/ ER+) breast cancer, a subset of the luminal B subtype, makes up approximately 10% of all breast cancers [1, 2]
Epidermal growth factor (EGF) binds EGFR, while heregulin (HRG) binds HER3 and HER4, and all three receptors dimerize with HER2 as the preferred co-receptor in HER2+ breast cancer cells, increasing HER2 activity [36]
We showed that the cross-regulation between HER2 and Trefoil factor 3 (TFF3) identifies TFF3 as a mediator of trastuzumab resistance in HER2+/ER+ breast cancer

Summary

Introduction

HER2/neu- and estrogen receptor α-positive (HER2+/ ER+) breast cancer, a subset of the luminal B subtype, makes up approximately 10% of all breast cancers [1, 2]. HER2+/ER+ breast cancer has recently been shown to be a heterogeneous subgroup, of which patients could benefit from trastuzumab with chemotherapy, combined anti-estrogen and HER2-targeted therapies, or even anti-estrogen alone [8, 12, 13]. The current treatment strategy for HER2+/ER+ breast cancer lacks defined standards to stratify patients to their respective optimum treatment, and fails to effectively predict for therapeutic resistance [8]. These findings reinforce the need to improve the current treatment strategy for HER2+/ER+ breast cancer [8]. The identification of novel biomarkers to predict treatment efficacy, and additional therapeutic targets to overcome drug resistance in HER2+/ER+ breast cancer, will be beneficial in facilitating the development of more efficacious therapies for the heterogeneous group of HER2+/ER+ breast cancer [8]

Methods

Results

Conclusion