Periostin blockade overcomes chemoresistance via restricting the expansion of mesenchymal tumor subpopulations in breast cancer

Youya Nakazawa,Fumihiro Sanada,Kay T Yeung,Jing Yang,Yoshiaki Taniyama,Shoji Nakamori,Ryuichi Morishita,Koji Morimoto

doi:10.1038/s41598-018-22340-7

Abstract

Recent studies suggest a functional involvement of Epithelial-Mesenchymal Transition (EMT) in tumor chemoresistance. Specifically, EMT is associated with chemoresistance and poor prognosis in triple-negative breast cancer. However, no effective therapy targeting EMT has been developed. Here, we report that periostin, an extracellular matrix protein, was induced upon chemotherapy and tightly correlated with the EMT gene signature and poor prognosis in breast cancer. In triple-negative breast cancer xenografts, chemotherapy upregulated periostin expression in tumor cells, triggered expansion of mesenchymal tumor cells and promoted invasion in residual tumors. Knockdown of periostin inhibited outgrowth and invasion of mesenchymal tumor cells upon chemotherapy. Furthermore, chemotherapy upregulated cancer-specific variants of periostin and application of a blocking antibody specifically targeting those variants overcame chemoresistance and halted disease progression without toxicity. Together, these data indicate that periostin plays a key role in EMT-dependent chemoresistance and is a promising target to overcome chemoresistance in triple-negative breast cancer.

Highlights

TNBC is an aggressive subtype of breast cancer that is closely related to basal-like breast cancer with a strong Epithelial-Mesenchymal Transition (EMT) gene signature with poor overall prognosis
MCF10DCIS cell line is derived from a premalignant epithelial breast tumor xenograft and lacks the expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2)
Since nCounter analysis system cannot quantitatively differentiate between human mRNAs from tumor cells and mouse mRNAs from stromal cells, we used qPCR analysis with human gene-specific primers to confirm that chemotherapies upregulated EMT-inducing transcription factors SNAI1/2 in residual tumor cells (Fig. 1B)

Summary

Introduction

TNBC is an aggressive subtype of breast cancer that is closely related to basal-like breast cancer with a strong EMT gene signature with poor overall prognosis. Due to a lack of estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER-2) expressions for targeted therapy in TNBC, its treatment largely consists of cytotoxic chemotherapies with anthracyclines and taxanes. A subset of TNBCs are responsive to initial chemotherapy, the probability of early relapse is significantly higher compared to other subtypes of breast cancer[1]. A number of studies showed that tumor cells undergo EMT to escape from chemotherapy and other targeted therapies. Therapeutic strategy targeting EMT has not been developed to overcome therapy resistance. Periostin overexpression and function have been implicated in several types of human cancer[9,10]. We set to determine the functional role of periostin in EMT-mediated chemoresistance in TNBC and to explore its clinical implications in overcoming chemoresistance in TNBC. 100 μm. (F) Periostin score before and after chemotherapy in 26 matched pair TNBC samples which showed residual disease after chemotherapy. ***P < 0.001, Wilcoxon signed-rank test

Methods

Results

Conclusion