The RNA-binding protein HuR regulates GATA3 mRNA stability in human breast cancer cell lines.

Meta-analyses of microarray data indicate that GATA3 is co-expressed with estrogen receptor alpha (ER) in breast cancer cells. While the significance of this remains unclear, it is thought that GATA3 may serve as a prognostic indicator in breast tumors and may play a role in ER signaling. Recently, reciprocal regulation of GATA3 and ER transcription was demonstrated, suggesting that control of their expression is intertwined.

Inhibition of de novo purine synthesis in human prostate cells results in ATP depletion, AMPK activation and induces senescence.

Background: 4-[2-(2-Amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4,6][1,4]thiazin-6-yl)-(S)-ethyl]-2,5-thienoylamino-l-glutamic acid (AG2034), is a classical antifolate shown to be an excellent inhibitor of glycinamide ribonucleotide formyltransferase (GARFT), ultimately inhibiting de novo purine synthesis. We examined some metabolic effects of this drug in prostate cancer cells, LNCaP, versus non-tumorigenic prostatic epithelial cells, RWPE-1.

Methods And Results: Cells were cultured in medium containing 10 nM 5-methyl-tetrahydrofolate supplemented with/without 1.

Timing is everything: order of administration of 5-aza 2' deoxycytidine, trichostatin A and tamoxifen changes estrogen receptor mRNA expression and cell sensitivity.

Restoration of estrogen receptor (ER) expression using epigenetic inhibitors re-establishes expression of the estrogen receptor (ER) and restores tamoxifen sensitivity in ER negative breast cancer cells. We tested if order of administration of the DNMT (5-aza 2' deoxycytidine/AZA) or HDAC (trichostatin A/TSA) inhibitors and tamoxifen affected ER re-expression and tamoxifen sensitivity. Treatment with AZA followed by co-administration of TSA plus tamoxifen resulted in the greatest ER re-expression and tamoxifen sensitivity, although sensitivity was not increased as robustly as expected.

Cytoplasmic accumulation of the RNA binding protein HuR is central to tamoxifen resistance in estrogen receptor positive breast cancer cells.

With prolonged exposure, a majority of estrogen receptor positive cancers develop resistance to tamoxifen and subsequent therapies including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). While much is known about overexpression of key growth promoting receptors including EGF, erbB2/Her2 and IGF receptors and subsequent activation of MAPK signaling associated with resistance, the underlying mechanism in the development of resistance still remains unknown. We found that inhibition of JNK, a member of the MAPK family, decreases cytoplasmic accumulation of the RNA binding protein HuR.

Trichostatin A and 5 Aza-2' deoxycytidine decrease estrogen receptor mRNA stability in ER positive MCF7 cells through modulation of HuR.

Trichostatin A (TSA) and 5-Aza 2'deoxycytidine (AZA), two well characterized pharmacologic inhibitors of histone deacetylation and DNA methylation, affect estrogen receptor alpha (ER) levels differently in ER-positive versus ER-negative breast cancer cell lines. Whereas pharmacologic inhibition of these epigenetic mechanisms results in re-expression and increased estrogen receptor alpha (ER) levels in ER-negative cells, treatment in ER-positive MCF7 cells results in decreased ER mRNA and protein levels. This decrease is dependent upon protein interaction with the ER 3'UTR.

A novel histone deacetylase inhibitor, scriptaid, enhances expression of functional estrogen receptor alpha (ER) in ER negative human breast cancer cells in combination with 5-aza 2'-deoxycytidine.

Epigenetic mechanisms, such as DNA methylation and histone deacetylation, may play a role in loss of estrogen receptor alpha (ER) expression in ER negative human breast cancer cells. Our previous studies showed that pharmacologic inhibition of these mechanisms using the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (AZA), and the histone deacetylase (HDAC) inhibitor, Trichostatin A (TSA), resulted in expression of functional ER mRNA and protein. Therefore, we sought to characterize the effects of a recently described HDAC inhibitor, Scriptaid, on cell growth and ER expression and function in ER negative human breast cancer cell lines.

The biology of breast carcinoma.

The biology of breast carcinoma is complex, with multiple factors contributing to its development and progression. The current review focuses on the role of several critical genes including estrogen receptor, progesterone receptor, retinoic acid receptor-beta, epidermal growth factor receptor family members, p53, BRCA1, and BRCA2 as risk factors for the development of disease, predictors of prognosis and response to therapy, and as therapeutic targets. Studies of the biology of these and other genes that contribute to the development and progression of breast carcinoma have had and will continue to have great impact on all aspects of disease management.