NCAPG confers trastuzumab resistance via activating SRC/STAT3 signaling pathway in HER2-positive breast cancer

Lili Jiang,Lan Wang,Xiangqin Kuang,Jianan Yang,Hongbiao Huang,Han Chen,Zhongqiu Zhou,Ning Hou,Liangliang Ren,Xuhong Chen,Zhuojun Zhang,Danping Huang,Wenhao Bao,Chun Lin,Jinyuan Pan,Libing Song

doi:10.1038/s41419-020-02753-x

Abstract

HER2+ breast cancer (BC) is characterized by rapid growth, early recurrence, early metastasis, and chemoresistance. Trastuzumab is the most effective treatment for HER2+ BC and effectively reduces the risk of recurrence and death of patients. Resistance to trastuzumab results in cancer recurrence and metastasis, leading to poor prognosis of HER2+ BC. In the present study, we found that non-structural maintenance of chromosome condensin 1 complex subunit G (NCAPG) expression was highly upregulated in trastuzumab-resistant HER2+ BC. Ectopic NCAPG was positively correlated with tumor relapse and shorter survival in HER2+ BC patients. Moreover, overexpression of NCAPG promoted, while silencing of NCAPG reduced, the proliferative and anti-apoptotic capacity of HER2+ BC cells both in vitro and in vivo, indicating NCAPG reduces the sensitivity of HER2+ BC cells to trastuzumab and may confer trastuzumab resistance. Furthermore, our results suggest that NCAPG triggers a series of biological cascades by phosphorylating SRC and enhancing nuclear localization and activation of STAT3. To summarize, our study explores a crucial role for NCAPG in trastuzumab resistance and its underlying mechanisms in HER2+ BC, and suggests that NCAPG could be both a potential prognostic marker as well as a therapeutic target to effectively overcome trastuzumab resistance.

Highlights

Breast cancer (BC) remains the leading cause of morbidity and mortality among cancers in females worldwide[1]
NCAPG is upregulated in trastuzumab-resistant BC The Cancer Genome Atlas (TCGA) data analysis displayed that NCAPG was markedly upregulated in BC tissues, in HER2+ cancer tissues (P < 0.001) (Fig. S1a, b)
NCAPG expression was significantly increased in the trastuzumab-resistant BC cell lines SKBR3/TR and BT474/TR compared to parental SKBR3 and BT474 cell lines (Fig. S2)

Summary

Introduction

Breast cancer (BC) remains the leading cause of morbidity and mortality among cancers in females worldwide[1]. BC accounts for 15–20% of total cases of BC, and is characterized by a high degree of malignancy and strong invasiveness, high resistance to chemotherapy, poor effectiveness of endocrine therapy, early recurrence and metastasis, and poor prognosis[4,5]. Trastuzumab, a humanized HER2-targeting drug, is the most effective treatment for HER2+ BC. Trastuzumab effectively reduces the risk of recurrence and death, extends the disease-free and non-progressive survival period, delays the recurrence time of metastasis, and prolongs survival in patients with metastasis[6,7]. The resistance rate of trastuzumab is 66–88% as a single agent and 20–50% when combined with chemotherapy in HER2+ BC, and trastuzumab resistance is the major cause of treatment failure resulting in relapse or death[8,9].

Methods

Results

Conclusion