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Tumor protein D52-like 2 contributes to proliferation of breast cancer cells.

ABSTRACT: Breast cancer is a major cause of cancer-related death among women. Tumor protein D52-like 2 (TPD52L2) is one member of the TPD52 family, which has been shown to function in mediating cell proliferation, apoptosis, and vehicle trafficking. TPD52 was originally identified in human breast carcinoma. In this study, the authors found that TPD52L2 is extensively expressed in multiple human breast cancer cell lines. To elucidate the functional role of TPD52L2 in breast cancer, the authors employed lentivirus-mediated short hairpin RNA (shRNA) to knock down TPD52L2 in one breast cancer cell line, ZR-75-30, which showed high TPD52L2 expression. The shRNA-mediated TPD52L2 knockdown inhibited the proliferation and colony formation in ZR-75-30 cells, as determined by MTT and colony formation assays. Knockdown of TPD52L2 led to an accumulation of cells in the G0/G1 phase of the cell cycle. Furthermore, knockdown of TPD52L2 promoted GSK3? phosphorylation in ZR-75-30 cells. This investigation indicates that TPD52L2 plays an essential role in the growth of breast cancer cells, which may contribute to provide gene therapy for breast cancer treatment.

SUBMITTER: Yang M

PROVIDER: S-EPMC5697702 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Tumor protein D52-like 2 contributes to proliferation of breast cancer cells.

Yang Mei M Wang Xueyao X Jia Jiaoyuan J Gao Hongwen H Chen Peng P Sha Xianliang X Wu Shan S

Cancer biotherapy & radiopharmaceuticals 20150128 1

Breast cancer is a major cause of cancer-related death among women. Tumor protein D52-like 2 (TPD52L2) is one member of the TPD52 family, which has been shown to function in mediating cell proliferation, apoptosis, and vehicle trafficking. TPD52 was originally identified in human breast carcinoma. In this study, the authors found that TPD52L2 is extensively expressed in multiple human breast cancer cell lines. To elucidate the functional role of TPD52L2 in breast cancer, the authors employed len ...[more]

PMID: 25629696

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Project description:BackgroundMaspin, which is classified as a tumor suppressor protein, is downregulated in many types of cancer. Several studies have suggested potential anti-proliferative activity of maspin as well as sensitizing activity of maspin for therapeutic cytotoxic agents in breast cancer tissue culture and animal models. All of the experimental data gathered so far have been based on studies with maspin localized cytoplasmically, while maspin in breast cancer tumor cells may be located in the cytoplasm, nucleus or both. In this study, the effect of maspin cytoplasmic and nuclear location and expression level on breast cancer proliferation and patient survival was studied.MethodsTissue sections from 166 patients with invasive ductal breast cancer were stained by immunohistochemistry for maspin and Ki-67 protein. The localization and expression level of maspin were correlated with estimated patient overall survival and percent of Ki-67-positive cells. In further studies, we created constructs for transient transfection of maspin into breast cancer cells with targeted cytoplasmic and nuclear location. We analyzed the effect of maspin location in normal epithelial cell line MCF10A and three breast cancer cell lines - MCF-7, MDA-MB-231 and SKBR-3 - by immunofluorescence and proliferation assay.ResultsWe observed a strong positive correlation between moderate and high nuclear maspin level and survival of patients. Moreover, a statistically significant negative relationship was observed between nuclear maspin and Ki-67 expression in patients with invasive ductal breast cancer. Spearman's correlation analysis showed a negative correlation between level of maspin localized in nucleus and percentage of Ki-67 positive cells. No such differences were observed in cells with cytoplasmic maspin. We found a strong correlation between nuclear maspin and loss of Ki-67 protein in breast cancer cell lines, while there was no effect in normal epithelial cells from breast. The anti-proliferative effect of nuclear maspin on breast cancer cells was statistically significant in comparison to cytoplasmic maspin.ConclusionsOur results suggest that nuclear maspin localization may be a prognostic factor in breast cancer and may have a strong therapeutic potential in gene therapy. Moreover, these data provide a new insight into the role of cytoplasmic and nuclear fractions of maspin in breast cancer.

Project description:PurposeClinical studies have shown that breast cancer risk is increased in hypertensive women. The underlying molecular mechanism remains undetermined. The current study tests our hypothesis that G protein coupled receptor kinase 4 (GRK4) is a molecule that links hypertension and breast cancer. GRK4 plays an important role in regulation of renal sodium excretion. Sustained activation of GRK4 as in the circumstances of single nucleotide polymorphism (SNPs) causes hypertension. Expression of GRK4 in the kidney is regulated by cMyc, an oncogene that is amplified in breast cancer.MethodsWestern analysis was used to evaluate GRK4 protein expression in seven breast cancer cell lines. GRK4 gene single nucleotide polymorphism in breast cancer cell lines and in breast cancer cDNA arrays were determined using TaqMan Genotyping qPRC. The function of GRK4 was evaluated in MCF-7 cells with cMyc knock-down and GRK4 re-expression and in MDA-MB-468 cells expressing inducible GRK4 shRNA lentivirus constructs. Nuclei counting and 5-Bromo-2'-deoxy-uridine (BrdU) labeling were used to evaluate cell growth and proliferation.ResultsGenotyping of GRK4 SNPs in breast cancer cDNA arrays (n = 94) revealed that the frequency of carrying two hypertension related SNPs A142 V or R65 L is threefold higher in breast cancer patients than in healthy people (P = 7.53E-11). GRK4 protein is expressed in seven breast cancer cell lines but not the benign mammary epithelial cell line, MCF-10A. Three hypertension related SNPs in the GRK4 gene were identified in the breast cancer cell lines. Except for BT20, all other breast cancer lines have 1-3 GRK4 SNPs of which A142 V occurs in all 6 lines. MDA-MB-468 cells contain homozygous A142 V and R65 L SNPs. Knocking down cMyc in MCF-7 cells significantly reduced the growth rate, which was rescued by re-expression of GRK4. We then generated three stable GRK4 knock-down MDA-MB-468 lines using inducible lentiviral shRNA vectors. Doxycycline (Dox) induced GRK4 silencing significantly reduced GRK4 mRNA and protein levels, growth rates, and proliferation. As a marker of cell proliferation, the percentage of BrdU-labeled cells decreased from 45 ± 3% in the cells without Dox to 32 ± 5% in the cells treated with 0.1 µg/mL Dox.ConclusionsGRK4 acts as an independent proliferation promotor in breast cancer. Our results suggest that targeted inhibition of GRK4 could be a new therapy for both hypertension and breast cancer.

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Tumor protein D52-like 2 contributes to proliferation of breast cancer cells.

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Tumor protein D52-like 2 contributes to proliferation of breast cancer cells.

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