CCAAT-displacement protein/cut homeobox transcription factor (CUX1) represses estrogen receptor-alpha (ER-α) in triple-negative breast cancer cells and can be antagonized by muscadine grape skin extract (MSKE).

08:00 EDT 9th April 2019 | BioPortfolio

Summary of "CCAAT-displacement protein/cut homeobox transcription factor (CUX1) represses estrogen receptor-alpha (ER-α) in triple-negative breast cancer cells and can be antagonized by muscadine grape skin extract (MSKE)."

Triple-Negative Breast Cancers (TNBCs) are the most difficult to treat subtype of breast cancer and are often associated with high nuclear expression of Snail and Cathepsin L (Cat L) protease. We have previously shown that Snail can increase Cat L expression/activity in prostate and breast cancer cells. This study investigated the role of CUX1 (a downstream substrate of Cat L) in TNBC. We showed that Cat L and CUX1 were highly expressed in TNBC patient tissue/cell lines, as compared to ER-positive samples, using cBioportal data and western blot/zymography analyses. Additionally, luciferase reporter and chromatin immunoprecipitation assays showed that CUX1 directly bound to estrogen receptor-alpha (ER-α) promoter in MDA-MB-468, a representative TNBC cell line, and that CUX1 siRNA could restore ER-α transcription and protein expression. Furthermore, Snail and CUX1 expression in various TNBC cell lines was inhibited by muscadine grape skin extract (MSKE, a natural grape product rich in anthocyanins) or Cat L inhibitor (Z-FY-CHO) leading to decreased cell invasion and migration. MSKE decreased cell viability and increased expression of apoptotic markers in MDA-MB-468 cells, with no effect on non-tumorigenic MCF10A cells. MSKE also decreased CUX1 binding to ER-α promoter and restored ER-α expression in TNBC cells, while both MSKE and CUX1 siRNA restored sensitivity to estradiol and 4-hydoxytamoxifen as shown by increased cell viability. Therefore, CUX1 activated by Snail-Cat L signaling may contribute to TNBC via ER-α repression, and may be a viable target for TNBC using natural products such as MSKE that targets cancer and not normal cells.


Journal Details

This article was published in the following journal.

Name: PloS one
ISSN: 1932-6203
Pages: e0214844


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Medical and Biotech [MESH] Definitions

A transcription factor characterized by N-terminal and C-terminal CYS2-HIS2 ZINC FINGERS separated by a homeobox. It represses the expression of E-CADHERIN to induce the EPITHELIAL-MESENCHYMAL TRANSITION. It also represses PROTO-ONCOGENE PROTEINS C-BCL-6; regulates the cell type-specific expression of SODIUM-POTASSIUM-EXCHANGING ATPASE; and promotes neuronal differentiation.

A transcription factor that consists of 8 CYS2-HIS2 ZINC FINGERS flanking a central HOMEOBOX. It binds to the 5'-CACCT-3' DNA sequence located within E-BOX ELEMENTS of many genes essential for embryonic growth and development and regulates their activity; it represses transcription of the E-CADHERIN gene. Mutations in the ZEB2 gene are associated with MOWAT-WILSON SYNDROME.

A homeobox-containing transcription factor that functions in heart development. Mutations in the NKX2-5 gene are associated with ATRIAL SEPTAL DEFECTS and TETRALOGY OF FALLOT.


An E2F transcription factor that represses GENETIC TRANSCRIPTION required for CELL CYCLE entry and DNA synthesis. E2F4 recruits chromatin remodeling factors indirectly to target gene PROMOTER REGIONS through RETINOBLASTOMA LIKE PROTEIN P130 and RETINOBLASTOMA LIKE PROTEIN P107.

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