SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis

Abstract

Metastatic dissemination of breast cancer cells represents a significant clinical obstacle to curative therapy. The loss of function of metastasis suppressor genes is a major rate-limiting step in breast cancer progression that prevents the formation of new colonies at distal sites. However, the discovery of new metastasis suppressor genes in breast cancer using genomic efforts has been slow, potentially due to their primary regulation by epigenetic mechanisms. Here, we report the use of model cell lines with the same genetic lineage for the identification of a novel metastasis suppressor gene, serum deprivation response (SDPR), localized to 2q32-33, a region reported to be associated with significant loss of heterozygosity in breast cancer. In silico metaanalysis of publicly available gene expression datasets suggests that the loss of expression of SDPR correlates with significantly reduced distant-metastasis–free and relapse-free survival of breast cancer patients who underwent therapy. Furthermore, we found that stable SDPR overexpression in highly metastatic breast cancer model cell lines inhibited prosurvival pathways, shifted the balance of Bcl-2 family proteins in favor of apoptosis, and decreased migration and intravasation/extravasation potential, with a corresponding drastic suppression of metastatic nodule formation in the lungs of NOD/SCID mice. Moreover, SDPR expression is silenced by promoter DNA methylation, and as such it exemplifies epigenetic regulation of metastatic breast cancer progression. These observations highlight SDPR as a potential prognostic biomarker and a target for future therapeutic applications.

Prognostic and Diagnostic Significance of SDPR-Cavin-2 in Hepatocellular Carcinoma

“…Evidence showed that cavin-2 (serum deprivation protein response, SDPR) was present in many cellular types, and down-regulated in several different cancers including breast, gastric, kidney, prostate and oral cancer [28,32]. In 2016, Ozturk et al [27] found that cavin-2 could be a potential prognostic biomarker and a therapeutic target for breast cancer. Therefore, it is particularly prospective to explore the application of cavin-2 in HCC.…”

“…Ozturk et al [27] suggested that the deletion of cavin-2 was likely to be mediated by promoter DNA hypermethylation during breast cancer progression. In 2016, Tian et al [34] found that cavin-2 suppressed cell proliferation and invasion in breast cancer cells by regulating epithelial-mesenchymal transition (EMT), with up-regulating epithelial markers (E-cadherin and β-catenin) and down-regulating mesenchymal markers (Vimentin and N-cadherin).…”

“…In oral squamous cell carcinomas, Unozawa et al [32] suggested that the ERK signaling pathway was attenuated frequently in the overexpression cavin-2 cells. In studied cancers, cavin-2 was a metastasis suppressor by inhibiting EMT, migration, and intravasation accompanied with promotion of apoptosis [27]. In HCC, numbers of studies reveal that it is believed that the EMT acts an important role, TGF-β signaling pathway and ERK signaling pathway have been considered as activators of cancer progression [35][36][37][38].…”

“…In 2013, Altintas et al [26] found that cavin-2 could be considered as genes protective against prostate cancer and involved in the early stages of prostate carcinogenesis. Meanwhile, previous studies indicated that the levels of cavin-2 were not only down-regulated in prostate cancer but also in kidney and breast cancers [27,28]. However, there has not been reported that the clinical and prognostic significance of cavin-2 expression in HCC.…”

Emerging Biological Principles of Metastasis

“…Metastatic carcinoma cells may also need to evade the actions of metastasis suppressor genes, which have been proposed to specifically block the later stages of the invasion-metastasis cascade (Steeg, 2003). Another alternative mechanism may involve defined epigenetic alterations that drive colonization, such as aberrant DNA methylation patterns (Ozturk et al, 2016). …”