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Cancer Lett ; 399: 29-43, 2017 07 28.
Article in English | MEDLINE | ID: mdl-28411130

ABSTRACT

Interferon induced transmembrane protein 1 (IFITM1) belongs to a family of interferon stimulated genes (ISGs) that is associated with tumor progression and DNA damage resistance; however, its role in endocrine resistance is not known. Here, we correlate IFITM1 expression with clinical stage and poor response to endocrine therapy in a tissue microarray consisting of 94 estrogen receptor (ER)-positive breast tumors. IFITM1 overexpression is confirmed in the AI-resistant MCF-7:5C cell line and not found in AI-sensitive MCF-7 cells. In this study, the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer are used to assess tumor growth and invasion in vivo. Lentivirus-mediated shRNA knockdown of IFITM1 in AI-resistant MCF-7:5C cells diminished tumor growth and invasion and induced cell death, whereas overexpression of IFITM1 in wild-type MCF-7 cells promoted estrogen-independent growth and enhanced their aggressive phenotype. Mechanistic studies indicated that loss of IFITM1 in MCF-7:5C cells markedly increased p21 transcription, expression and nuclear localization which was mediated by JAK/STAT activation. These findings suggest IFITM1 overexpression contributes to breast cancer progression and that targeting IFITM1 may be therapeutically beneficial to patients with endocrine-resistant disease.


Subject(s)
Antigens, Differentiation/metabolism , Antineoplastic Agents, Hormonal/pharmacology , Aromatase Inhibitors/pharmacology , Breast Neoplasms/drug therapy , Cell Movement/drug effects , Cell Proliferation/drug effects , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Drug Resistance, Neoplasm , Janus Kinases/metabolism , STAT1 Transcription Factor/metabolism , Adult , Aged , Aged, 80 and over , Animals , Antigens, Differentiation/genetics , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cyclin-Dependent Kinase Inhibitor p21/genetics , Down-Regulation , Enzyme Activation , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Mice, Inbred NOD , Mice, SCID , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Neoplasm Staging , RNA Interference , Retrospective Studies , Signal Transduction/drug effects , Transcription, Genetic , Transfection , Xenograft Model Antitumor Assays
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