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Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-? signaling.

ABSTRACT: Serum deprivation response (SDPR), a key substrate for protein kinase C, play a critical role in inducing membrane curvature and participate in the formation of caveolae. However, the function of SDPR in cancer development and progression is still not clear. Here, we found that SDPR is downregulated in human breast cancer. Overexpression of SDPR suppresses cell proliferation and invasion in MDA-MB-231 cells, while depletion of SDPR promotes cell proliferation and invasion in MCF10A cells. Subsequently, SDPR depletion induces epithelial-mesenchymal transition (EMT)-like phenotype. Finally, knockdown of SDPR activates transforming growth factor-? (TGF-?) signaling by upregulation of TGF-?1 expression. In conclusion, our results showed that SDPR inhibits breast cancer progression by blocking TGF-? signaling. Serum deprivation response suppresses cell proliferation and invasion in breast cancer cells. SDPR depletion induces epithelial-mesenchymal transition by activation of TGF-? signaling.

SUBMITTER: Tian Y

PROVIDER: S-EPMC4814251 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-β signaling.

Tian Yao Y Yu Yue Y Hou Li-Kun LK Chi Jiang-Rui JR Mao Jie-Fei JF Xia Li L Wang Xin X Wang Ping P Cao Xu-Chen XC

Cancer science 20160213 3

Serum deprivation response (SDPR), a key substrate for protein kinase C, play a critical role in inducing membrane curvature and participate in the formation of caveolae. However, the function of SDPR in cancer development and progression is still not clear. Here, we found that SDPR is downregulated in human breast cancer. Overexpression of SDPR suppresses cell proliferation and invasion in MDA-MB-231 cells, while depletion of SDPR promotes cell proliferation and invasion in MCF10A cells. Subseq ...[more]

PMID: 26749136

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Project description:This study helps to define the implications of breast cancer anti-estrogen resistance 3 (BCAR3) in breast cancer and extends the current understanding of its molecular mechanism of action. BCAR3 has been shown to promote cell proliferation, migration and attachment to extracellular matrix components. However, in a cohort of metastatic breast cancer patients who received tamoxifen treatment, high BCAR3 mRNA levels were associated with favorable progression-free survival outcome. These results suggest that, besides its established roles, BCAR3 may have additional mechanisms of action that regulate breast cancer aggressive phenotype. In this study, we investigated whether BCAR3 is a novel antagonist of the canonical transforming growth factor ? (TGF?) pathway, which induces potent migration and invasion responses in breast cancer cells.We surveyed functional genomics databases for correlations between BCAR3 expression and disease outcomes of breast cancer patients. We also studied how BCAR3 could regulate the TGF?/Smad signaling axis using Western blot analysis, coimmunoprecipitation and luciferase assays. In addition, we examined whether BCAR3 could modulate TGF?-induced cell migration and invasion by using an automated imaging system and a confocal microscopy imaging-based matrix degradation assay, respectively.Relatively low levels of BCAR3 expression in primary breast tumors correlate with poor distant metastasis-free survival and relapse-free survival outcomes. We also found a strong correlation between the loss of heterozygosity at BCAR3 gene alleles and lymph node invasion in human breast cancer, further suggesting a role for BCAR3 in preventing disease progression. In addition, we found BCAR3 to inhibit Smad activation, Smad-mediated gene transcription, Smad-dependent cell migration and matrix digestion in breast cancer cells. Furthermore, we found BCAR3 to be downregulated by TGF? through proteasome degradation, thus defining a novel positive feedback loop mechanism downstream of the TGF?/Smad signaling pathway.BCAR3 is considered to be associated with aggressive breast cancer phenotypes. However, our results indicate that BCAR3 acts as a putative suppressor of breast cancer progression by inhibiting the prometastatic TGF?/Smad signaling pathway in invasive breast tumors. These data provide new insights into BCAR3's molecular mechanism of action and highlight BCAR3 as a novel TGF?/Smad antagonist in breast cancer.

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Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-? signaling.

Publications

Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-β signaling.

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