Cavin3 Suppresses Breast Cancer Metastasis via Inhibiting AKT Pathway.

Xin An,Jiabin Lu,Hua Zhu,Bingchuan Geng,Yanxia Shi,Xi Lin,Zhicheng Xiang,Qiwei Jiang,Shusen Wang,Anli Yang,Mayan Huang,Zhongyu Yuan

doi:10.3389/fphar.2020.01228

Abstract

ObjectiveCavin3 is a putative tumor suppressor protein. However, its molecular action on tumor regulation is largely unknown. The aim of the current study is to explore the implication of cavin3 alteration, its clinical significance, and any potential molecular mechanisms in the regulation of breast cancer (BC).MethodsTCGA (The Cancer Genome Atlas) and GTEx (Genotype-Tissue Expression) data bases, and 17 freshly paired BC and adjacent normal tissues were analyzed for mRNA levels of Cavin3. Furthermore, cavin3 protein expression from 407 primary BC samples were assessed by immunohistochemistry (IHC) and measured by H-score. The clinical significance of cavin3 expression was explored by Kaplan-Meier analysis and the Cox regression method. In vitro biological assays were performed to elucidate the function and underlying mechanisms of cavin 3 in BC cell lines.Results Cavin3 mRNA was dramatically down-regulated in BC compared with the negative control. The median H-score of cavin3 protein by IHC was 50 (range 0-270). There were 232 (57%) and 175 (43%) cases scored as low (H-score≤50) and high (H-score >50) levels of cavin3, respectively. Low cavin3 was correlated with a higher T and N stage, and worse distant metastasis-free survival (DMFS) and overall survival (OS). Multivariate survival analysis revealed low cavin3 was an independent fact for worse DMFS. In BC cells, an overexpression of cavin3 could inhibit cell migration and invasion, and significantly decreased the level of p-Akt. Knockout of cavin3, meanwhile, promoted cell invasion ability and increased the level of p-AKT.ConclusionCavin3 expression is significantly lower in BC and is correlated with distant metastasis and worse survival. Cavin3 functions as a metastasis suppressor via inhibiting the AKT pathway, suggesting cavin3 as a potential prognostic biomarker and a target for BC treatment.

Highlights

Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in women worldwide (DeSantis et al, 2016; Bray et al, 2018)
We first analyzed The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) datasets and found expression of Cavin3 mRNA was significantly lower in BC tumors compared with normal tissues, P
Cavin3 mRNA levels were further analyzed in 17 paired freshfrozen breast tumor and tumor-adjacent tissues collected in Sun YatSen University Cancer Center (SYSUCC), which showed the relative Cavin3 mRNA leves to bactin were significantly lower in 14 out of 17 pairs of BC tissues compared with normal control, P=0.0047(Figure 1C)

Summary

Introduction

Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in women worldwide (DeSantis et al, 2016; Bray et al, 2018). Distant metastases account for more than 90% of BC death. Increasing evidence indicates the important role of caveolin and cavin family members in cancer regulation. They are regarded as new “tumor and metastasis-modifying genes” which might be targeted in cancer therapies (Gupta et al, 2014; MartinezOutschoorn et al, 2015). Heterogeneity expression patterns and paradoxical roles of these proteins on tumor suppression and oncogenesis have been reported on different tumor types and stages (Zhang et al, 2008; Di Vizio et al, 2009; Witkiewicz et al, 2009a), suggesting the dual role of these caveolin and cavin family members in cancer regulation

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Results

Conclusion