Combined p53- and PTEN-deficiency activates expression of mesenchyme homeobox 1 (MEOX1) required for growth of triple-negative breast cancer
| Autor: | Miao-Chia Lo, Hui Jiang, Duxin Sun, Chang-Ching Lin, Mari Gasparyan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
STAT5B Triple Negative Breast Neoplasms Mice SCID Biochemistry Mice 03 medical and health sciences Breast cancer Mice Inbred NOD STAT5 Transcription Factor medicine Animals Humans Tensin PTEN Molecular Biology Triple-negative breast cancer Cell Proliferation Homeodomain Proteins TYK2 Kinase Gene knockdown 030102 biochemistry & molecular biology biology Cell growth PTEN Phosphohydrolase Molecular Bases of Disease Cell Biology medicine.disease Gene Expression Regulation Neoplastic 030104 developmental biology Cancer cell Cancer research biology.protein Female Tumor Suppressor Protein p53 STAT6 Transcription Factor Transcription Factors |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra119.010710 |
| Popis: | Triple-negative breast cancer (TNBC) is an aggressive cancer subtype for which effective therapies are unavailable. TNBC has a high frequency of tumor protein p53 (Tp53/p53)- and phosphatase and tensin homolog (PTEN) deficiencies, and combined p53- and PTEN-deficiency is associated with poor prognosis and poor response to anticancer therapies. In this study, we discovered that combined p53- and PTEN-deficiency in TNBC activates expression of the transcription factor mesenchyme homeobox 1 (MEOX1). We found that MEOX1 is expressed only in TNBC cells with frequent deficiencies in p53 and PTEN, and that its expression is undetectable in luminal A, luminal B, and HER2+ subtypes, as well as in normal breast cells with wild-type (WT) p53 and PTEN. Notably, siRNA knockdown of both p53 and PTEN activated MEOX1 expression in breast cancer cells, whereas individual knockdowns of either p53 or PTEN had only minimal effects on MEOX1 expression. MEOX1 knockdown abolished cell proliferation of p53- and PTEN-deficient TNBC in vitro and inhibited tumor growth in vivo, but had no effect on the proliferation of luminal and HER2+ cancer cells and normal breast cells. RNA-Seq and immunoblotting analyses showed that MEOX1 knockdown decreased expression of tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 5B (STAT5B), and STAT6 in p53- and PTEN-deficient TNBC cells. These results reveal the effects of combined p53- and PTEN-deficiency on MEOX1 expression and TNBC cell proliferation, suggesting that MEOX1 may serve as a potential therapeutic target for managing p53- and PTEN-deficient TNBC. |
| Databáze: | OpenAIRE |
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