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1.  Epithelial ovarian cancer: An overview 
Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.
PMCID: PMC4267287  PMID: 25525571
Epithelial ovarian cancer; Breast cancer type 1; Chemotherapy
2.  Triple Negative Breast Cancer – An Overview 
Hereditary genetics : current research  2013;2013(Suppl 2):001.
Triple Negative Breast Cancer (TNBC) is a heterogeneous disease that based on immunohistochemistry (IHC) is estrogen receptor (ER) negative, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative. TNBC is typically observed in young AA women and Hispanic women who carry a mutation in the BRCA1 gene. TNBC is characterized by a distinct molecular profile, aggressive nature and lack of targeted therapies. The purpose of this article is to review the current and future novel signalling pathways as therapeutic approaches to TNBC. Recent Identification of a new BRCA1 trafficking pathway holds promise in the future for the development of targeted therapies for TNBC.
PMCID: PMC4181680  PMID: 25285241
3.  Mitochondrial localization, ELK-1 transcriptional regulation and Growth inhibitory functions of BRCA1, BRCA1a and BRCA1b proteins 
Journal of cellular physiology  2009;219(3):634-641.
BRCA1 is a tumor suppressor gene that is mutated in families with breast and ovarian cancer. Several BRCA1 splice variants are found in different tissues, but their subcellular localization and functions are poorly understood at the moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis and function as a tumor suppressor of triple negative breast, ovarian and prostate cancers. In this study we have analyzed the function of BRCA1 isoforms (BRCA1a and BRCA1b) and compared them to the wild type BRCA1 protein using several criteria like studying expression in normal and tumor cells by RNase protection assays, sub cellular localization/fractionation by immunofluorescence microscopy and western blot analysis, transcription regulation of biological relevant proteins and growth suppression in breast cancer cells. We are demonstrating for the first time that ectopically expressed GFP-tagged BRCA1, BRCA1a, and BRCA1b proteins are localized to the mitochondria, repress ELK-1 transcriptional activity and possess antiproliferative activity on breast cancer cells. These results suggest that the exon 9,10 and 11 sequences (aa 263 – 1365) which contain two nuclear localization signals, p53, Rb, c-Myc, γ- tubulin, Stat, Rad 51, Rad 50 binding domains, angiopoietin-1 repression domain are not absolutely required for mitochondrial localization and growth suppressor function of these proteins. Since mitochondrial dysfunction is a hallmark of cancer, we can speculate that the mitochondrial localization of BRCA1 proteins may be functionally significant in regulating both the mitochondrial DNA damage as well as apoptotic activity of BRCA1 proteins and mislocalization causes cancer.
PMCID: PMC3693557  PMID: 19170108
BRCA1/1a/1b proteins; breast cancers; mitochondria; growth suppression; transcriptional regulation; ELK-1
4.  BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9 
Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP, RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers.
PMCID: PMC3433105  PMID: 22957306
BRCA1; BRCA1a; Ubc9; Ovarian cancer; RING domain mutants; nuclear import; Growth suppression
5.  Ubc9 Mediates Nuclear Localization and Growth Suppression of BRCA1 and BRCA1a Proteins 
Journal of Cellular Physiology  2011;226(12):3355-3367.
BRCA1 gene mutations are responsible for hereditary breast and ovarian cancers. In sporadic breast tumors, BRCA1 dysfunction or aberrant subcellular localization is thought to be common. BRCA1 is a nuclear–cytoplasm shuttling protein and the reason for cytoplasmic localization of BRCA1 in young breast cancer patients is not yet known. We have previously reported BRCA1 proteins unlike K109R and cancer-predisposing mutant C61G to bind Ubc9 and modulate ER-α turnover. In the present study, we have examined the consequences of altered Ubc9 binding and knockdown on the subcellular localization and growth inhibitory function of BRCA1 proteins. Our results using live imaging of YFP, GFP, RFP-tagged BRCA1, BRCA1a and BRCA1b proteins show enhanced cytoplasmic localization of K109 R and C61G mutant BRCA1 proteins in normal and cancer cells. Furthermore, down-regulation of Ubc9 in MCF-7 cells using Ubc9 siRNA resulted in enhanced cytoplasmic localization of BRCA1 protein and exclusive cytoplasmic retention of BRCA1a and BRCA1b proteins. These mutant BRCA1 proteins were transforming and impaired in their capacity to inhibit growth of MCF-7 and CAL51 breast cancer cells. Interestingly, cytoplasmic BRCA1a mutants showed more clonogenicity in soft agar and higher levels of expression of Ubc9 than parental MCF7 cells. This is the first report demonstrating the physiological link between cytoplasmic mislocalization of mutant BRCA1 proteins, loss of ER-α repression, loss of ubiquitin ligase activity and loss of growth suppression of BRCA1 proteins. Thus, binding of BRCA1 proteins to nuclear chaperone Ubc9 provides a novel mechanism for nuclear import and control of tumor growth.
PMCID: PMC3329759  PMID: 21344391
6.  Molecular Mechanism of Activation of Transforming Growth Factor Beta/Smads Signaling Pathway in Ets Related Gene-Positive Prostate Cancers 
Transforming growth factor beta (TGF-β) signaling pathway is involved in diverse cellular processes, including cell proliferation, differentiation, adhesion, apoptosis, and some human diseases including cancer. Smad proteins function as mediators of intracellular signal transduction of TGF-β. Following their phosphorylation by TGF-β receptor I, Smad2 and Smad3 form a heteromeric complex with Smad4 and then are translocated into the nucleus where they bind to other co-factors and regulate the expression of target genes. ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors. Chromosomal rearrangement of TMPRSS2 gene and ERG gene has been found in the majority of prostate cancers. Over-expression of full length or truncated ERG proteins is associated with a higher rate of recurrence and unfavorable prognosis. In this review, we focus on recent understanding of regulation of TGF-β/Smads signaling pathway by ERG proteins in prostate cancer.
PMCID: PMC4322943
TGF-β; Smad3; Phosphorylation; ERG; TMPRSS2-ERG
7.  Anti-Epileptic Drug Targets Ewing Sarcoma 
Ewing Sarcoma (ES) is a rare form of bone cancer that most commonly affects children and adolescents. Chromosomal translocations are fundamental to the development of Ewing Sarcoma, linked to the changes in gene expression affecting transcription factors. Histone acetyl transferases (HATs) and histone deacetylases (HDACs) regulate transcription by modifying acetylation of both histones and transcription factors. Despite the use of multimodal therapeutic approaches current therapies are associated with significant short and long-term side effects. Hence, new therapeutic approaches are needed. In this study, we show that ERG/EWS-ERG, inhibits transcriptional activation properties of RXRα. These results suggest that ERG/EWS-ERG/EWS-Fli-1 may target transcriptional co-activators and transcriptional repressors and thereby regulate RXRα transcriptional activity. To understand the molecular mechanism of action, how the fusion protein targets nuclear receptor function, and to provide a clue for the cancer health disparity seen in Ewing Sarcoma, we hypothesized that the aberrant fusion protein, EWS-ERG/EWS-Fli-1 regulates HDACs-mediated repressor complex and inhibits the binding of transcriptional activator complex causing transcriptional repression of RXRα activity. Since it is known that HDACs regulate nuclear receptors, we proposed that HDAC inhibitor, valproic acid (VPA), an anti-epileptic drug, may reverse the inhibitory properties of EWS-ERG/EWS-Fli-1 oncoprotein on RXRα transcriptional activity and might therefore be used as therapeutic agent in ES. We demonstrate that VPA reverses the inhibitory effect of EWSERG/EWS-Fli-1 on RXRα transcriptional activity and also inhibits the cell growth. Furthermore, VPA induces apoptosis and restored the expression of RXRα target genes RARβ, CRABPII and p21 activity and repressed the expression of aberrant fusion proteins, EWS-ERG and EWS-Fli-1 in Ewing Sarcoma cells. Thus, therapeutic regulation of transcriptional repressor properties of EWS-ERG/EWS-Fli-1 with an anti-epileptic drug with a promising new potential might have a profound impact on prevention, management and treatment of Ewing Sarcoma. Therapeutic use of VPA in minority patients may help reduce the health disparity.
PMCID: PMC4316750  PMID: 25664332
Ewing Sarcoma; Valproic Acid; Histone Deacetylase; EWS-ERG; EWS-Fli-1; Retinoid X Receptor α
8.  Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells 
International Journal of Oncology  2011;39(1):111-119.
An ETS family member, ETS Related Gene (ERG) is involved in the Ewing family of tumors as well as leukemias. Rearrangement of the ERG gene with the TMPRSS2 gene has been identified in the majority of prostate cancer patients. Additionally, overexpression of ERG is associated with un- favorable prognosis in prostate cancer patients similar to leukemia patients. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate transcription as well as epigenetic status of genes through acetylation of both histones and transcription factors. Deregulation of HATs and HDACs is frequently seen in various cancers, including prostate cancer. Many cellular oncogenes as well as tumor viral proteins are known to target either or both HATs and HDACs. Several studies have demonstrated that there are alterations of HDAC activity in prostate cancer cells. Recently, we found that ERG binds and inhibits HATs, which suggests that ERG is involved in deregulation of protein acetylation. Additionally, it has been shown that ERG is associated with a higher expression of HDACs. In this study, we tested the effect of the HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) on ERG-positive prostate cancer cells (VCaP). We found that VPA and TSA induce apoptosis, upregulate p21/Waf1/CIP1, repress TMPRSS2-ERG expression and affect acetylation status of p53 in VCaP cells. These results suggest that HDAC inhibitors might restore HAT activity through two different ways: by inhibiting HDAC activity and by repressing HAT targeting oncoproteins such as ERG.
PMCID: PMC3329756  PMID: 21519790
valproic acid; trichostatin A; histone deacetylase; histone acetyltransferase; CBP/p300; p53; ETS related gene; prostate cancer

Results 1-8 (8)