Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer

Parl, Fritz F.

doi:10.1038/sj.tpj.6500201

Cited by 24 publications

(16 citation statements)

References 12 publications

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“…Finally, to rule out failure of the long-range 14-kb GSTM1 assay resulting from poor DNA quality as a possible cause of erroneous genotyping, we developed a separate long-range assay of the ER␣ gene. Consistent with earlier studies, every DNA sample tested contained the 14-kb ER␣ fragment, including ϩ/ϩ, ϩ/Ϫ, and Ϫ/Ϫ samples, confirming DNA integrity (15,16).…”

Section: Discussionsupporting

confidence: 88%

“…We chose the ER␣ gene at 6q25.1 and designed primers to amplify a 14-kb fragment in exon and intron 4 of the ER␣ gene. In earlier studies, we had shown that the ER␣ gene is present in all of the breast cancers, including those that do not express the ER␣ protein (15,16). We applied the assay to all of the ϩ/ϩ samples and 50 randomly chosen ϩ/Ϫ and Ϫ/Ϫ samples and obtained the ER␣ fragment in every instance (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Association of Homozygous Wild-Type Glutathione S-Transferase M1 Genotype with Increased Breast Cancer Risk

Roodi¹,

Dupont

Moore

et al. 2004

Cancer Research

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More than 500 studies have examined the association of the glutathione S-transferase M1 (GSTM1) genotype with various malignancies yielding inconsistent results. The genotyping was based on a PCR assay that identified the GSTM1 null (؊/؊) genotype but did not distinguish homozygous wild-type (؉/؉) and heterozygous (؉/؊) individuals. We developed an assay that allowed the definition of ؉/؉, ؉/؊, and ؊/؊ genotypes by separate identification of wild-type and null alleles, which were found with frequencies of 0.225 and 0.775, respectively, in Caucasian women. We applied the new assay to a breast cancer case-control study and identified the ؉/؉ genotype in 14 (6.9%) of 202 control subjects compared with 37 (18.2%) of 203 patients. Compared with women with the ؊/؊ genotype, the relative risk of breast cancer for the ؉/؉ genotype was 2.83 (95% confidence interval, 1.45-5.59; P ‫؍‬ 0.002), suggesting a protective effect of the GSTM1 deletion.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Association of Homozygous Wild-Type Glutathione S-Transferase M1 Genotype with Increased Breast Cancer Risk

Roodi¹,

Dupont

Moore

et al. 2004

Cancer Research

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“…In this respect, the absence of ERa gene expression has been associated with the aberrant methylation of its CpG islands in a significant fraction of breast cancers (Weigel & deConinck 1993, Ottaviano et al 1994. Recent data indicate that chromatin inactivation mediated by histone deacetylation and DNA methylation are indeed critical components of ERa silencing in human breast cancer cells (Parl 2003). In vitro studies have shown that DNA (cytosine-5) methyltransferase (DNMT1) interacts physically with either histone deacetylase 1 (HDAC1) or histone deacetylase 2 (HDAC2) and that co-treatment with DNMT1 and HDAC inhibitors can synergistically induce ERa gene expression in ERa-negative breast cancer cells , Rountree et al 2000, Yang et al 2001.…”

Section: Alterations In Era and Pgr Expression Or Functionmentioning

confidence: 99%

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Normanno

Maïo

Maio

et al. 2005

Endocr Relat Cancer

258

224

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Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogenindependent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor a (ERa) and/or increased non-genomic activity of ERa, estrogen supersensitivity, increased growth factor signaling, suppression of ERa expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

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“…About 30% of tumors are ERaÀ at diagnosis, while a proportion of ERaþ tumors lack the receptor at the time of tamoxifen relapse in the adjuvant or metastatic setting. It is already established that the ERa gene is silenced via CpG island methylation or histone deacetylation in a proportion of clinical breast cancers that are ERaÀ on presentation (Parl 2003). Indeed, Yang et al (2001) have shown that ERa negativity in the MDA-MB-231 and -435 cell lines can be partially reversed by the DNA methyl transferase 1 (DNMT1) inhibitor, aza-2-deoxycytidine (5-aza-dC) and by the histone deacetylase (HDAC) inhibitor, trichostatin (TSA), an event that restores some estrogen responsiveness from ERE reporter constructs and has obvious therapeutic implications for the future treatment of some ERaÀ patients.…”

Section: Endocrine-related Cancermentioning

confidence: 99%

Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy

Nicholson¹,

Staka²,

Boyns³

et al. 2004

Endocr Relat Cancer

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There is an increasing body of evidence demonstrating that elevated growth signaling in breast cancer cells can promote forms of endocrine resistance in either an estrogen receptor-dependent or -independent manner. The current article reviews what is known about such growth factor signaling networks and resistance to estrogen withdrawal and considers the many novel therapeutic opportunities that stem from this knowledge.

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Multiple mechanisms of estrogen receptor gene repression contribute to ER-negative breast cancer

Cited by 24 publications

References 12 publications

Association of Homozygous Wild-Type Glutathione S-Transferase M1 Genotype with Increased Breast Cancer Risk

Association of Homozygous Wild-Type Glutathione S-Transferase M1 Genotype with Increased Breast Cancer Risk

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy

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