Biomedical subjects
Publications and source records attributed to Thomas C Hamilton.
Improving the prognosis of ovarian cancer patients is a major challenge to scientists and clinicians. At a recent multidisciplinary meeting in Washington DC, advances in identification of precursor lesions, progress in disease biomarkers and animal models, the promise of nanotechnology, and strategies for manipulation of the innate and adaptive immune response offered prospects for real progress in this difficult-to-treat disease.
Animal models of ovarian cancer are crucial for understanding the pathogenesis of the disease and for testing new treatment strategies. A model of ovarian carcinogenesis in the rat was modified and improved to yield ovarian preneoplastic and neoplastic lesions that pathogenetically resemble human ovarian cancer. A significantly lower dose (2 to 5 mug per ovary) of 7,12-dimethylbenz(a)anthracene (DMBA) was applied to the one ovary to maximally preserve its structural integrity. DMBA-induced mutagenesis was additionally combined with repetitive gonadotropin hormone stimulation to induce multiple cycles of active proliferation of the ovarian surface epithelium. Animals were treated in three arms of different doses of DMBA alone or followed by hormone administration. Comparison of the DMBA-treated ovaries with the contralateral control organs revealed the presence of epithelial cell origin lesions at morphologically distinct stages of preneoplasia and neoplasia. Their histopathology and path of dissemination to other organs are very similar to human ovarian cancer. Hormone cotreatment led to an increased lesion severity, indicating that gonadotropins may promote ovarian cancer progression. Point mutations in the Tp53 and Ki-Ras genes were detected that are also characteristic of human ovarian carcinomas. Additionally, an overexpression of estrogen and progesterone receptors was observed in preneoplastic and early neoplastic lesions, suggesting a role of these receptors in ovarian cancer development. These data indicate that this DMBA animal model gives rise to ovarian lesions that closely resemble human ovarian cancer and it is adequate for additional studies on the mechanisms of the disease and its clinical management.
OBJECTIVES: Previously, we demonstrated that the LOT1 (PLAGL1/ZAC1) gene encodes a zinc-finger transcription factor and has growth suppressive effects in carcinoma cell lines. The gene is localized on chromosome 6q24-25, a common site for loss of heterozygosity (LOH) in many solid tumors including ovarian cancer. In this study, we evaluated the LOT1 gene expression and allelic deletion in the tumor tissues in order to provide additional evidence to support the gene's potential role in cancer. METHODS: The LOT1 gene expression was analyzed in malignant ovarian epithelium obtained from frozen human ovarian tumor tissues using laser capture microdissection (LCM) and real-time PCR techniques. Highly frequent single nucleotide polymorphic (SNP) sites within the LOT1 gene were identified and used for PCR and direct sequencing to determine the occurrence of allelic imbalance in a series of surgically resected ovarian and breast carcinomas. RESULTS: The analysis revealed that LOT1 mRNA expression was not detectable in 12 of 31 (39%) cases of ovarian cancer and was variable between the remaining 19 tumor specimens. These findings are consistent with the previous data that showed altered expression of LOT1 in different human ovarian carcinoma cell lines. In addition, we analyzed the occurrence of LOT1 allelic deletion in different ovarian tumor genomic DNA samples that included papillary serous (majority), mucinous, and primary peritoneal adenocarcinomas of low- to high-grade and the corresponding normal lymphocytes. The informative samples showed 12 out of 33 or about 36.4% LOH of this gene based on allelic loss of one or more polymorphic sites within the LOT1 genomic sequences. Similarly, primary breast carcinomas, which included invasive ductal (majority), spindle cell, mucinous, giant cell, and atypical medullary carcinomas, were examined on genomic DNA from patients for the allelic loss of LOT1. The informative cases showed 4 out of 10 samples or 40% LOH of this candidate tumor suppressor gene locus in breast cancer. CONCLUSIONS: The altered expression and LOH of the LOT1 locus support the gene's potential role, at least in part, in the pathogenesis of ovarian cancer and possibly in other types of cancer.
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BACKGROUND: The authors suggested that the loss of collagen IV and laminin-containing basement membrane and the loss of Disabled-2 (Dab2) expression were two critical events associated with morphologic dysplastic changes of the ovarian surface epithelium as a step in tumorigenicity. Both the basement membrane and Dab2, a candidate tumor suppressor of ovarian carcinoma, were involved in epithelial cell surface positioning and organization. The authors speculated that the purging of the basement membrane may be similar to the proteolysis during gonadotropin-stimulated ovulation, a cyclooxygenase 2 (Cox-2)-mediated process. METHODS: Prophylactic oophorectomy is used to prevent breast and ovarian carcinoma in high-risk populations. These ovarian tissue specimens often contain an increased presence of morphologically abnormal lesions that are believed to be preneoplastic. The authors evaluated archived prophylactic oophorectomy specimens to verify whether the loss of Dab2 expression and the removal of the basement membrane that occur at the ovarian surface and inclusion cyst epithelia are molecular markers of preneoplastic lesions. Of the 36 samples containing identifiable ovarian surface epithelial components on slides, immunostaining was employed to evaluate the intactness of the basement membrane (periodic acid-Schiff [PAS], collagen IV, and laminin) and the expression of Dab2 and Cox-2. Expression of Cox-1 and Cox-2 also were evaluated in cultured ovarian surface epithelial cells prepared from ovarian tissue specimens removed from patients who underwent prophylactic surgery. RESULTS: The morphologically normal ovarian surface epithelium typically contained a collagen IV- and laminin-positive basement membrane, which also was detected by PAS staining. Many morphologically altered areas, such as papillomatosis, invaginations, inclusion cysts, stratification, adenomas, and microscopic adenocarcinomas, were found in these specimens. Both the morphologically altered and adjacent morphologically normal epithelia consistently exhibited loss of basement membrane and/or Dab2 expression and an increase in Cox-2 staining. Frequently, an increase in Cox-2 staining was correlated with the loss of epithelial basement membrane in morphologically normal areas. CONCLUSIONS: The loss of Dab2 and basement membrane and the overexpression of Cox-2 were observed in presumptive neoplastic precursor areas of oophorectomy specimens obtained from a population at high risk for ovarian carcinoma. Transient loss of collagen IV and laminin in the basement membrane of the preneoplastic epithelium and the loss of Dab2 expression are common early events associated with morphologic alteration and tumorigenicity of the ovarian surface epithelium. The authors concluded that Cox-2 overexpression may play a role in the purging of basement membrane of the ovarian surface epithelium, mimicking the process of ovulation. Further experiments may be able to test the hypothetical model derived from these histologic observations.
Tumor cells often appear in a deviant differentiated stage, and dedifferentiation is a hallmark of malignancy; however, the causative mechanism of the global changes in dedifferentiation is not understood. The GATA transcription factors function in cell lineage specification during embryonic development and organ formation. The transcriptional targets of the GATA factors in early embryonic development include Disabled-2 and collagen IV, markers for epithelial lineages. GATA-4 and GATA-6 are expressed strongly and are localized in the nucleus in ovarian surface epithelial cells in tissues or primary cell cultures. By immunohistochemistry, we found that 82% of the 50 tumors analyzed had lost GATA-6 function, either by a complete absence of expression or by cytoplasmic mislocalization. The frequent loss of GATA-6 was also confirmed in a panel of ovarian surface epithelial and tumor cell lines. Although GATA-4 is absent only in a small percentage (14%) of ovarian tumors, it is lost in the majority of established cell lines in culture. The loss of GATA-6 correlates with the loss of Disabled-2, collagen IV, and laminin, markers for epithelial cell types. Loss of GATA factors was also found in an in vitro model for spontaneous transformation of rat ovarian epithelial cells. Repression of GATA-6 by small interfering (si)RNA approach in cultured cells leads to dedifferentiation as indicated by the loss of Disabled-2 and laminin expression. Restoration of GATA factors expression by ectopic transfection suppresses cell growth and is incompatible with the maintenance of the cells in culture. However, restoration of GATA-4 and GATA-6 expression is not able to induce expression of endogenous Disabled-2 in tumor cells, suggesting that the loss of GATA factors and dedifferentiation are irreversible processes. In conclusion, we observed the inappropriate expression and cellular localization of the GATA transcription factors in ovarian tumor tissues and cancer cell lines, and we have demonstrated that down-regulation of GATA factor expression leads to dedifferentiation. We propose that alterations of GATA transcription factor expression and aberrant nucleocytoplasmic localization may contribute to the anomalous epithelial dedifferentiation of the ovarian tumor cells.
Alteration in epidermal growth factor receptor (EGFR) family signaling is among the most frequently implicated effectors of human oncogenesis. Overexpression of members of this family of receptors has often been detected in many epithelial tumors and is believed to be associated with an overall poor prognosis in patients with cancer. Therefore, we hypothesized that identification of potential EGF target genes in normal cells will provide a basis for unbiased genetic analysis of this signaling pathway in cancer. We utilized Atlas Rat 1.2 nylon cDNA arrays (Clontech) to determine gene expression changes in normal rat ovarian surface epithelial (ROSE) cells following EGF treatment. The results indicate activation of genes involved in a wide variety of cellular mechanisms, including regulation of cell cycle and proliferation, apoptosis, and protein turnover. In addition, using an in vitro model of ovarian cancer, we demonstrated that malignant transformation of ROSE cells resulted in alteration of downstream effectors of the EGFR pathway, as exemplified by aberrant expression of p66Shc, c-Jun, c-Myc, c-Fos, Lot1, p21Cip/Waf, and cdc25A. These data suggest that knowledge of the downstream genetic lesions, which may result in loss of growth factor requirement of the affected cells, will be crucial for the selection of the EGFR pathway as an effective target for cancer therapy.
Ovarian cancer is the leading cause of death among women from gynecological malignancies inthe United States. Resistance to the chemotherapeutic agent cisplatin isa major limitation for the successful treatment of ovarian cancer. In an effort to overcome the cisplatin resistance problem in ovarian cancer treatment, we have sought to enhance cisplatin cytotoxicity by perturbing the nucleotide excision repair (NER) pathway. The NER pathway is responsible for repairing cisplatin bound to DNA. Expression of one of the NER components, ERCC1, is correlated with cisplatin drug resistance. Hence, we targeted ERCC1 by antisense RNA methodologies, and we show that we could sensitize a relatively sensitive A2780 cell line and also the highly resistant OVCAR10 cell line to cisplatin by expressing antisense ERCC1 RNA in them as measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The A2780 cell lines expressing antisense ERCC1 had 1.9-8.1-fold enhancements in cisplatin sensitivity. The OVCAR10 antisense ERCC1 cell lines had IC(50) values ranging from 2.28 microM to 2.7 microM cisplatin as compared with 9.52 micro M for control OVCAR10 cells. The OVCAR10 antisense ERCC1 cells also show reduced DNA-damage repair capacity as assessed by host cell reactivation. Furthermore, immunocompromised mice transplanted with the antisense cell lines survived longer than the mice bearing control cells after response to cisplatin treatment. These data suggest that it is possible to substantially enhance the cisplatin cytotoxicity by disturbing the NER pathway in cisplatin-resistant cell lines and to enhance the survival capacity of mice in an ovarian cancer xenograft model.
In women, >80% of malignant ovarian tumors are of epithelial origin. Early detection of these tumors is very challenging,and extensive i.p. dissemination is common by the time of diagnosis. The lack of adequate geneticmouse models of ovarian carcinomas significantly delays advances in early detection and treatment. We report that female transgenic mice expressing the transforming region of SV40 under control of the Mullerian inhibitory substance type II receptor gene promoter develop bilateral ovarian tumors in approximately 50% of cases. Histologically, these tumors are poorly differentiated carcinomas with occasional cysts and papillary structures present at the surface of the ovary. These tumors disseminate i.p., invade omentum, and form ascites as do human ovarian carcinomas. The epithelial origin of these tumors is supported by detection of cytokeratins 8 and 19, and the absence of alpha-inhibin, a protein characteristically expressed in normal granulosa cells and most granulosa cell tumors. Cell lines derived from the ascites exhibit the properties of epithelial ovarian cancer, such as anchorage-independent growth, tumorigenicity in immunocompromised mice, expression of epithelial cell markers, and organotropic implantation. The availability of a transgenic mouse model of disseminated ovarian carcinoma and respective cell lines should advance our understanding of this neoplasm, and serve as a useful tool for the evaluation of emerging detection and treatment strategies.
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OBJECTIVE: The ovarian-specific promoter, OSP-1, which was cloned from the transcript of a rat retrovirus-like element specifically expressed in ovarian tissue, was tested for its ability to drive ovary-specific transcription in transgenic mice. METHODS: Transgenic mice were generated with the lacZ reporter gene (OSP-lacZ) or the early region of SV40 virus (OSP-TAg) placed under the control of the OSP-1 promoter. OSP-lacZ and OSP-TAg transgenic animals were examined, respectively, for the expression of lacZ (OSP-lacZ) or the development of tumors (OSP-TAg). RESULTS: The expression of lacZ in the resulting OSP-lacZ mice was restricted to the ovary as determined by X-gal staining of multiple organs. Immunohistochemical detection of beta-galactosidase showed lacZ expression mainly in the granulosa cells and ovarian surface epithelial cells. OSP-TAg mice developed tumors in a variety of tissues, including unilateral granulosa cell tumors in two of three female founder mice. In the contralateral ovary of one mouse with a granulosa cell tumor, there were alterations in the ovarian surface epithelial cells suggestive of preneoplasia. CONCLUSIONS: Although the OSP-1 promoter was able to restrict reporter gene expression to the ovary in transgenic mice, the expression of TAg in the OSP-TAg mice resulted in ovarian tumors as well as tumors in numerous other organs. This indicated that although transcription from the OSP-1 promoter occurs predominantly in the ovary, this promoter is sufficiently leaky in cells in other tissues to permit their tumorigenic conversion by SV40 TAg.
PURPOSE: We have previously found that cellular retinol-binding protein 1 (CRBP1),involved in retinol transport and metabolism, is down-regulated in an in vitro rat model of ovarian cancer and in several human ovarian cancer cell lines. The aim of this study was to determine the clinical relevance of this change to human ovarian cancer. EXPERIMENTAL DESIGN: A cohort of 48 frozen human serous ovarian carcinomas was evaluated for CRBP1 gene expression. Malignant ovarian epithelial cells were selectively procured by laser capture microdissection, and their CRBP1 expression was determined by real-time PCR. Immunohistochemistry for CRBP1 was performed on paraffin sections of ovarian tumors using polyclonal affinity-purified rabbit anti-CRBP1 antibody. RESULTS: In 35% of ovarian cancer patient samples, there was no detectable CRBP1 expression by real-time PCR. The expression of CRBP1 in microdissected serous ovarian carcinomas was not related to either tumor stage (P = 0.6839) or grade (P = 0.9599). Quantitative PCR results were confirmed by immunohistochemistry using an antibody against CRBP1. CONCLUSIONS: The loss of CRBP1 expression in clinical ovarian tumor specimens is consistent with our previous findings in the rat model and human ovarian cancer cell lines. It appears to be an early event in ovarian carcinogenesis because there was no statistically significant difference in its frequency between tumor stages and grades. Our findings suggest that the loss of CRBP1 expression contributes to the ovarian cancer oncogenesis via altered vitamin A metabolism.
LOT1 is a zinc-finger nuclear transcription factor, which possesses anti-proliferative effects and is frequently silenced in ovarian and breast cancer cells. The LOT1 gene is localized at chromosome 6q24-25, a chromosomal region maternally imprinted and linked to growth retardation in several organs and progression of disease states such as transient neonatal diabetes mellitus. Toward understanding the molecular mechanism underlying the loss of LOT1 expression in cancer, we have characterized the genomic structure and analyzed its epigenetic regulation. Genome mapping of LOT1 in comparison with the other splice variants, namely ZAC1 and PLAGL1, revealed that its mRNA ( approximately 4.7 kb; GenBank accession number U76261) is potentially spliced using six exons spanning at least 70 kb of the human genome. 5'-RACE (rapid amplification of cDNA ends) data indicate the presence of at least two transcription start sites. We found that in vitro methylation of the LOT1 promoter causes a significant loss in its ability to drive luciferase transcription. To determine the nature of in vivo methylation of LOT1, we used bisulfite-sequencing strategies on genomic DNA. We show that in the ovarian and breast cancer cell lines and/or tumors the 5'-CpG island of LOT1 is a differentially methylated region. In these cell lines the ratio of methylated to unmethylated CpG dinucleotides in this region ranged from 31 to 99% and the ovarian tumors have relatively higher cytosine methylation than normal tissues. Furthermore, we show that trichostatin A, a specific inhibitor of histone deacetylase, relieves transcriptional silencing of LOT1 mRNA in malignantly transformed cells. It appears that, unlike DNA methylation, histone deacetylation does not target the promoter, and rather it is indirect and may be elicited by a mechanism upstream of the LOT1 regulatory pathway. Taken together, the data suggest that expression of LOT1 is under the control of two epigenetic modifications and that, in the absence of loss of heterozygosity, the biallelic (two-hit) or maximal silencing of LOT1 requires both processes.
The signal transduction adapter protein Disabled-2 (Dab2) is one of the two mammalian orthologs of the Drosophila Disabled. The brain-specific Disabled-1 (Dab1) functions in positional organization of brain cells during development. Dab2 is widely distributed and is highly expressed in many epithelial cell types. The dab2 gene was interrupted by in-frame insertion of beta-galactosidase (LacZ) in embryonic stem cells and transgenic mice were produced. Dab2 expression was first observed in the primitive endoderm at E4.5, immediately following implantation. The homozygous Dab2-deficient mutant is embryonic lethal (earlier than E6.5) due to defective cell positioning and structure formation of the visceral endoderm. In E5.5 dab2 (-/-) conceptus, visceral endoderm-like cells are present in the deformed primitive egg cylinder; however, the visceral endoderm cells are not organized, the cells of the epiblast have not expanded, and the proamniotic cavity fails to form. Disorganization of the visceral endodermal layer is evident, as cells with positive visceral endoderm markers are scattered throughout the dab2 (-/-) conceptus. Only degenerated remains were observed at E6.5 for dab2 (-/-) embryos, and by E7.5, the defective embryos were completely reabsorbed. In blastocyst in vitro culture, initially cells with characteristics of endoderm, trophectoderm, and inner cell mass were observed in the outgrowth of the hatched dab2 (-/-) blastocysts. However, the dab2 (-/-) endodermal cells are much more dispersed and disorganized than those from wild-type blastocysts, the inner cell mass fails to expand, and the outgrowth degenerates by day 7. Thus, Dab2 is required for visceral endodermal cell organization during early mouse development. The absence of an organized visceral endoderm in Dab2-deficient conceptus leads to the growth failure of the inner cell mass. We suggest that Dab2 functions in a signal pathway to regulate endodermal cell organization using endocytosis of ligands from the blastocoel cavity as a positioning cue.
BACKGROUND: Ovarian surface epithelial cells are positionally organized as a single cell layer by a sheet of basement membrane. It is believed that the contact of the ovarian surface epithelial cells with the basement membrane regulates cell growth and ensures the organization of the epithelium. Disabled-2 (Dab2), a signal transduction protein and a candidate tumor suppressor of ovarian carcinoma, functions in positional organization of ovarian surface epithelial cells. In ovarian carcinomas, genetic and epigenetic changes enable the tumor cells to escape positional control and proliferate in a disorganized fashion. Alterations in the extracellular environment may also be critical for tumor initiation and progression. METHODS: We analyzed and compared the presence of collagen IV and laminin, the scaffold proteins of the basement membrane, and Dab2 in 50 ovarian tumors that are restricted to the ovaries and in 50 metastases of ovarian tumors by immunohistochemistry. Expression of collagen IV, laminin, and Dab2 was also analyzed by Northern blotting in a panel of human ovarian surface epithelial and cancer cell lines. RESULTS: The basement membrane is often absent in morphologically benign ovarian surface and cyst epithelium and low-grade tumors and collagen IV and laminin are absent in the extracellular matrix of most of the primary tumors tested. Of the 50 ovarian tumors confined to the ovaries, 6% (3 of 50) were collagen IV positive and 24% (12 of 50) were laminin positive tumors. Of the 50 metastatic tumors, 16% (8 of 50) are collagen IV positive and 86% (43 of 50) are laminin positive. In addition, even in the metastatic ovarian tumors that are largely collagen IV negative, there are pockets of local areas in which the tumor cells are surrounded by collagen IV-positive staining. Dab2 is absent in the majority of ovarian tumors found in both ovaries and metastatic sites. In both nontumorigenic human ovarian surface epithelial and cancer cell lines, collagen IV, laminin, and Dab2 are expressed aberrantly. CONCLUSIONS: Loss of the basement membrane may be an early event in the preneoplastic transformation of ovarian surface epithelium and in the early stages of tumorigenesis before tumor invasion and metastasis. The majority of primary ovarian tumors examined lack collagen IV and laminin in their extracellular matrix. However, expression of laminin is restored in the majority of metastatic tumors. Reexpression of collagen IV may also contribute to tumor metastasis. The ability of tumor cells to dynamically alter the expression of collagen IV and laminin may facilitate the shedding of cancer cells into the peritoneal spaces and subsequent attachment to the metastatic sites. We propose that loss of collagen IV and laminin may be an initial event in ovarian tumorigenicity and that restoration of collagen IV and laminin expression in the later stages of tumor development may promote metastasis of ovarian tumors.
BACKGROUND: Disabled-2 (Dab2), a candidate tumor suppressor of ovarian carcinoma, frequently (around 80%) loses its expression in ovarian tumors. Expression of exogenous Dab2 in tumor cell lines negatively regulates growth and suppresses the downstream signal of the Ras/mitogen activated protein kinase mitogenic pathway. The inactivation of Dab2 is believed to be an early event in ovarian tumorigenicity. METHODS: The authors analyzed the correlation among expression of Dab2, presence of basement membrane (collagen IV and laminin), morphologic alteration of the surface epithelial cells, and expression of the mitotic index marker Mib-1 in 50 archived ovarian tumors by an immunohistochemical approach. The stainings of Dab2, Mib-1, collagen IV, and laminin in premalignant lesions bordering both normal and neoplastic ovarian surface epithelium from adjacent slides were analyzed in 50 ovarian tumors. RESULTS: In these 50 ovarian tumors, the percentage of Mib-1 positive tumor cells distributed in a wide range, from 1% to 75%, and there has no strong correlation with the expression of Dab2. However, in the premalignant regions bordering tumor and normal ovarian surface epithelium, the loss of Dab2 expression closely correlated with the dysplastic morphologic transition and Mib-1 expression of the ovarian surface epithelial cells. In 20 foci in 12 out of the 50 tumors, a transition from normal to neoplastic morphology within a contiguous epithelium was observed, and in all cases the morphologic change correlated with the loss of Dab2 staining. In addition, the collagen and laminin staining of the basement membrane were absent or weakened in pre-malignant epithelium prior to loss of Dab2 expression in all these 20 cases. Nevertheless, collagen IV and laminin were detectable in established adenomas on the same tumor slides. CONCLUSIONS: The loss of Dab2 is closely associated with the transition of ovarian surface epithelial cells to premalignant states and is likely involved in the initiation of ovarian tumorigenicity. Transient loss of collagen IV and laminin in the basement membrane of the premalignant epithelium and subsequent inactivation of Dab2 are common early events associated with tumorigenicity of the ovarian surface epithelium.
Human ovarian cancer cell lines derived from A2780 by stepwise exposure to increasing cisplatin concentrations show progressive resistance to cisplatin. Previous studies have shown increased cellular glutathione and elevated steady-state expression of gamma-glutamylcysteine synthetase (gamma-GCS) and of the transcription factor c-Jun, all in proportion to the level of resistance in the resistant cells. We hypothesized that c-Jun was an important locus of control of the detoxicating enzymes mediating resistance, and that resistance reversal would be achieved by specific inhibition of this mechanism. A2780 (sensitive) and C30 (resistant) cells were treated with a 20-mer c-jun phosphorothioate antisense oligodeoxynucleotide (ISIS 10582, 1 microM), and a decrease in steady-state c-jun mRNA was demonstrated in the resistant cells. The expression of gamma-GCS mRNA was down-regulated and the cellular level of glutathione was decreased in C30 cells. No change in gamma-GCS expression occurred in A2780 cells. Using the microtetrazolium (MTT) cytotoxicity assay, we determined that the c-jun antisense decreased the IC50 value for cisplatin in C30 cells from 18.2 to 3.7 microM, and had a substantially smaller effect in A2780 cells. To determine if c-jun overexpression alone could confer resistance to the sensitive cell line, we transiently transfected A2780 cells with a c-jun expression vector. The transfected cells exhibited a 10.7-fold elevation of glutathione (GSH) content, a 9.2-fold increase in c-Jun protein content, and a 2-fold increase in the IC50 for cisplatin. These data suggest that altered regulation of transcription factor expression contributes to the acquired resistance phenotype in these ovarian cancer cells, and provide a novel potential target for therapeutic intervention.