Cavin3 Suppresses Breast Cancer Metastasis via Inhibiting AKT Pathway

Abstract

Objective: Cavin3 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). Methods: TCGA (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 (Hscore >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. Conclusion: Cavin3 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.

Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response

“…Loss of cavin3 expression is more prevalent in late-stage/high-grade cancers than in early-stage/low-grade cancers ( An et al, 2020 ; Carén et al, 2011 ; Lee et al, 2008 ; Wikman et al, 2012 ). Cavin3 expression is lost due to promoter methylation in numerous cancer types ( Lee et al, 2008 ; Lee et al, 2011 ; Martinez et al, 2009 ; Tong et al, 2010 ; Xu et al, 2001 ; Zöchbauer-Müller et al, 2005 ).…”

“…Loss of cavin3 expression is more prevalent in late-stage/high-grade cancers than in earlystage/low-grade cancers (An et al, 2020;Caren et al, 2011;Lee et al, 2008;Wikman et al, 2012).…”

Editorial: Chemo-Radiation-Resistance in Cancer Therapy

“…Identifying metastasis-associated genes and finding effective targets is the main strategy to prevent metastasis and improve survival of breast cancer. On the explore of putative tumor suppressor protein, Xin An et al ( An et al, 2020 ) confirmed that Cavin3 expression is significantly downregulated in breast cancer, and correlated with distant metastasis and worse survival. Cavin3 functions as a metastasis suppressor by downregulating the Akt pathway, which suggests that cavin3 can be a potential prognostic biomarker and a target for breast cancer treatment.…”