Anne T. Ferguson's research while affiliated with Johns Hopkins University and other places

Publications (16)

Article
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Formation of transcriptional repression complexes such as DNA methyltransferase (DNMT) 1/histone deacetylase (HDAC) or methyl-CpG binding protein/HDAC is emerging as an important mechanism in silencing a variety of methylated tissue-specific and imprinted genes. Our previous studies showed that treatment of estrogen receptor (ER)-alpha-negative hum...
Article
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We have identified 14-3-3 σ (σ) as a gene whose expression is lost in breast carcinomas, primarily by methylation-mediated silencing. In this report, we investigated the timing of loss of σ gene expression during breast tumorigenesis in vivo. We analysed the methylation status of σ in breast cancer precursor lesions using microdissection for select...
Article
Full-text available
Recent findings have established a connection between DNA methylation and transcriptionally inactive chromatin characterized by deacetylated histones. Because the absence of estrogen receptor alpha (ERalpha) gene expression has been associated with aberrant methylation of its CpG island in a significant fraction of breast cancers, we tested whether...
Article
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Traditionally, scientists have focused on structural changes in DNA sequences, such as mutations and deletions, as the cause for altered patterns of gene expression in human cancer. However, a recent explosion of studies indicates that epigenetic changes can be equally important in controlling gene expression. For example, global changes in DNA met...
Article
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Expression of 14-3-3 final sigma (final sigma) is induced in response to DNA damage, and causes cells to arrest in G(2). By SAGE (serial analysis of gene expression) analysis, we identified final sigma as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. We verified this finding by Northern blot ana...
Article
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Retinoic acid (RA)-resistance in breast cancer cells has been associated with irreversible loss of retinoic acid receptor beta, RARbeta, gene expression. Search of the causes affecting RARbeta gene activity has been oriented at identifying possible differences either at the level of one of the RARbeta promoters, RARbeta2, or at regulatory factors....
Article
Full-text available
Expression of 14-3-3 () is induced in response to DNA damage, and causes cells to arrest in G2. By SAGE (serial analysis of gene expression) analysis, we identified as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. We verified this finding by Northern blot analysis. Remarkably, mRNA was undetecta...
Article
Full-text available
Estrogen receptor (ER)-negative breast cancer cells display extensive methylation of the ER gene CpG island and elevated DNA methyltransferase (DMT) expression compared to ER-positive cells. The present study demonstrates that DMT protein levels tightly correlate with S phase fraction in ER-positive cells, whereas ER-negative cells express DMT thro...
Article
Full-text available
Several methods have been used recently to determine gene expression profiles of cell populations. Here we demonstrate the strength of combin- ing two approaches, serial analysis of gene expression (SAGE) and DNA arrays, to help elucidate pathways in breast cancer progression by finding genes consistently expressed at different levels in primary br...
Article
Progesterone receptor (PR) is an estrogen-stimulated gene which has a CpG island that is heavily methylated in a significant fraction of estrogen receptor (ER)-negative/PR-negative human breast cancers and cell lines, including MDA-MB-231 cells. Treatment of MDA-MB-231 cells with the demethylating agent, 5-aza-2'-deoxycytidine (deoxyC) led to demet...
Article
Estrogen and estrogen receptor (ER) play an important role in the development and function of the mammary gland. During mammary gland development, the hypothalamus and pituitary gland signal changes in the level of plasma estrogen, which is associated with proliferation of the mammary epithelial cells, leading to branching of ducts and formation of...
Article
Full-text available
The cytosine analog 5-aza-2'-deoxycytidine is a potent inhibitor of DNA methyltransferase. Its cytotoxicity has been attributed to several possible mechanisms including reexpression of growth suppressor genes and formation of covalent adducts between DNA methyltransferase and 5-aza-2'-deoxycytidine-substituted DNA which may lead to steric inhibitio...
Article
Estrogen receptor alpha (ER) plays a key role in the development and progression of breast cancer as well as the treatment and outcome of breast cancer patients. In normal mammary epithelial cells, the level of ER fluctuates during the menstrual cycle in response to cyclical changes in estrogen. However, in breast cancer normal control of ER gene e...
Article
Full-text available
Hormonal factors have a profound influence on the development, treatment, and outcome of breast cancer. The absence of steroid hormone receptors is highly correlated with resistance to antihormonal treatments. Work in cultured human breast cancer cell lines has shown that the absence of estrogen receptor (ER) gene expression in ER- cells is associa...
Article
Approximately one third of breast cancers grow independently of estrogen, lack detectable estrogen receptor (ER) protein, and rarely respond to hormonal treatment. Previous studies correlated the lack of ER gene expression in ER-negative breast tumor cells with hypermethylation of a CpG island in the 5' region of the ER gene. In order to determine...

Citations

... is type of epigenetic reprogramming can occur before the development of pathologically detectable lesions [4,5]. Risk stratification/early detection of breast cancer could be improved by the incorporation of biomarkers that reflect molecular changes associated with carcinogenesis [6]. ...
... 14-3-3ơ was originally identified as a human mammary epithelium marker 1 and as a tumor suppressor gene (13,14), which was determined to be reduced or lost in numerous types of solid tumor (15). Loss or reduction of 14-3-3σ by CpG methylation or p53 mutation contributes to the progression of different types of carcinomas, including early stages of tumor development (16)(17)(18)(19)(20)(21). This suggests that the function of 14-3-3σ may help prevent the malignant transformation of epithelial cells. ...
... 14-3-3ơ was originally identified as a human mammary epithelium marker 1 and as a tumor suppressor gene (13,14), which was determined to be reduced or lost in numerous types of solid tumor (15). Loss or reduction of 14-3-3σ by CpG methylation or p53 mutation contributes to the progression of different types of carcinomas, including early stages of tumor development (16)(17)(18)(19)(20)(21). This suggests that the function of 14-3-3σ may help prevent the malignant transformation of epithelial cells. ...
... Estrogen receptor-α (ER-α), a ligand-dependent transcription factor, 1 has an important role in sexual development, reproductive functions, neuroendocrine functions, cardiovascular functions and carcinogenesis in breast. [2][3][4][5] Although a subset of non-proliferating epithelial cells express ER-α in rodent and human mammary glands, 6,7 ER-α is indispensable for the growth and morphogenesis of the adult mammary gland. 8 Consequently, studies suggested that the ER-α-mediated activation of paracrine signaling pathways 9,10 may promote proliferation of neighboring ER-α-negative epithelial cells and morphogenesis in mammary gland. ...
... BFB administration caused significant upregulation in the ESR-α gene in DMBA/BFB and BFB groups that may restore the sensitivity to hormonal treatment. It has been reported that the treatment of ESR-negative breast cancer cells with hypomethylating agents results in the re-expression of active ESR [53]. Such results suggest the investigation of the concomitant use of the BFB along with TAM in treating the TAM-resistant breast cancer. ...
... The effect of lower doses of DNMTi is DNA demethylation and the reexpression of silenced genes, possibly those associated with cell proliferation, DNA repair, apoptosis, and senescence. At higher doses of DNMTi, DNMT is trapped to DNA and forms covalent adducts [32,33], triggering DNA damage response and subsequent cytotoxicity. Current evidence indicates that when low-doses of DNMTi are given, methylation is blocked but the dose is not cytotoxic [17][18][19]. ...
... However, at puberty, development is directed by hormonal signals in females, leading to ductal morphogenesis, while the mammary anlage atrophies in the male (1). During pregnancy and subsequent lactation, a hormonal surge leads to intensive elaboration of the mammary epithelium, in part through the mitogenic action of estradiol (1)(2)(3). At the molecular level, these physiologic changes in the gland during puberty, pregnancy and lactation result from the action of ligand-dependent nuclear hormone receptors (4)(5)(6) leading to transcriptional activation of target genes (7)(8)(9)(10). ...
... Additionally, ERα expression is epigenetically silenced by DNA methyltransferase or histone deacetylases in the ESR1 promoter of TNBC cells, leading to an aggressive phenotype and the failure of endocrine therapy 19 . Several studies have shown that reexpression of functional ERα by treatment with DNMT and HDAC inhibitors resulted in significant growth inhibition in TNBC cells 20,21 . Furthermore, although it was recently terminated, a clinical trial aimed at reactivating ERα, which can be targeted by antiestrogen agents, by a combination of DNMT and HDAC inhibitors to patients with TNBC has been conducted (ClinicalTrials.gov, ...
... Furthermore, their combinations with other anticancer drugs are being validated as therapeutic options for various solid cancers such as ovarian, colon, and lung cancer [71]. Intriguingly, estrogen receptor (ER) or progesterone receptor (PR) was shown to be epigenetically silenced by DNMT and HDAC in BC, which could be restored by the application of epi-drugs [253,254]. Recently, a comprehensive study on assessing the effects of decitabine in breast cancer revealed a range of responses to decitabine that could not be predicted based on mechanisms like demethylation of tumor suppressor genes and viral mimicry response [255]. Furthermore, they demonstrated that while decitabine induces genome-wide expression changes and demethylation using transcriptome and methylome analysis, these effects are not necessarily paired and do not correlate with sensitivity. ...
... [6][7][8][9] Survivin is overexpressed in several cancers [10][11][12][13][14] and is the fourth most highly expressed protein in human cancer tissues compared to normal control tissues. 15 Survivin dysregulates apoptosis by blocking caspase activation and also alters sensitivity to antitumor drugs, resulting in disease survival or recurrence. 5 Owing to its indisputable role in cancer, blocking the survivin oncogene or factors that stabilize the survivin protein by various immunotherapeutic or molecular approaches are promising therapeutic strategies in cancer. ...