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Activating Transcription Factor-5 Knockdown Reduces Aggressiveness of Mammary Tumor Cells and Attenuates Mammary Tumor Growth.

ABSTRACT: Activating transcription factor-5 (ATF5) is an anti-apoptotic factor and has been implicated in enhancing the survival of cancer cells under stress and in regulating the autophagy process. Targeting ATF5 in anticancer therapy may be particularly attractive because of its differential role in cancer cells than in non-transformed cells, thus allowing specificity of the treatment. Using the delivery of short hairpin RNA vectors into the Mvt1 and Met1 cell lines, we tested the role of ATF5 in the development of mammary tumors in vivo and in regulating proliferation and migration of these cells in vitro. In this study, we demonstrate that knockdown of ATF5 (ATF5-KD) in both cell lines results in a decreased tumor volume and weight, as well as in a reduced proliferation rate and migratory potential of the cells. In addition, ATF5-KD led to an increased autophagy flux and a shift in the sub-populations comprising Mvt1 cells from the aggressive CD24-positive cells toward less aggressive CD24-negative cells. Taken together, these findings suggest that ATF5 plays an important role in enhancing mammary tumor cells overall aggressiveness and in promoting mammary tumor growth and emphasize the possible benefit of anti-ATF5 therapy in breast cancer patients, particularly, against tumors characterized with the positive expression of cell surface CD24.

SUBMITTER: Ben-Shmuel S

PROVIDER: S-EPMC5519529 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Activating Transcription Factor-5 Knockdown Reduces Aggressiveness of Mammary Tumor Cells and Attenuates Mammary Tumor Growth.

Ben-Shmuel Sarit S Rashed Rola R Rostoker Ran R Isakov Elina E Shen-Orr Zila Z LeRoith Derek D

Frontiers in endocrinology 20170721

Activating transcription factor-5 (ATF5) is an anti-apoptotic factor and has been implicated in enhancing the survival of cancer cells under stress and in regulating the autophagy process. Targeting ATF5 in anticancer therapy may be particularly attractive because of its differential role in cancer cells than in non-transformed cells, thus allowing specificity of the treatment. Using the delivery of short hairpin RNA vectors into the Mvt1 and Met1 cell lines, we tested the role of ATF5 in the de ...[more]

PMID: 28785242

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Project description:A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414-13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674-18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292-13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097-14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers, as well as novel therapeutic targets.

Dataset Information

Activating Transcription Factor-5 Knockdown Reduces Aggressiveness of Mammary Tumor Cells and Attenuates Mammary Tumor Growth.

Publications

Activating Transcription Factor-5 Knockdown Reduces Aggressiveness of Mammary Tumor Cells and Attenuates Mammary Tumor Growth.

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