Estrogen Receptor Gene Analysis in Estrogen Receptor-Positive and Receptor-Negative Primary Breast Cancer

Roodi, Nady; Bailey, Lisa; Kao, Woei‐Yau; Verrier, Carmel S.; Yee, Cindy J.; Dupont, William D.; Parl, Fritz F.

doi:10.1093/jnci/87.6.446

Cited by 230 publications

(157 citation statements)

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“…It has been estimated that only 1 % of primary breast tumors contain missense mutations of the ER gene [94]. These mutations may be more frequent in metastatic breast lesions and could affect normal ER function.…”

Section: Mutants With Point Mutationmentioning

confidence: 99%

Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion

Platet

Cathiard

Gleizes

et al. 2004

Critical Reviews in Oncology/Hematology

318

236

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Estrogens play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially breast epithelial cells, through interaction with two nuclear estrogen receptors (ER and ERIn this review, we present a brief overview of the actions of estrogens in the different steps of breast carcinogenesis, including cancer progression to metastasis, and of their clinical consequences in the prevention, prognosis and treatment of the disease. The requirement of estrogen receptors, mainly of the alpha subtype, in normal mammary gland differentiation and growth has been evidenced by estrogen receptor deficiency in animals. The promotion of breast cancer carcinogenesis by prolonged exposure to estrogens is well-documented and this has logically led to the use of antiestrogens as potentially chemopreventive agents. In breast cancer progression, however, the exact roles of estrogen receptors have been less well established but they may possibly be dual. Estrogens are mitogenic in ER-positive cells and antiestrogens are an efficient adjuvant therapy for these tumors. On the other hand, the fact that estrogens and their receptors protect against cancer cell invasiveness through distinct mechanisms in experimental models may explain why the presence of ER is associated with well-differentiated and less invasive tumors.2

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Section: Mutants With Point Mutationmentioning

confidence: 99%

Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion

Platet

Cathiard

Gleizes

et al. 2004

Critical Reviews in Oncology/Hematology

318

236

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“…The absence of ERa does not appear to be a result of mutations that are found in less than 1% of ER-negative tumors (Roodi et al, 1995;Lacroix et al, 2004). Moreover, in ERa-negative breast cancer cells, silencing of the ERa gene is accompanied by alteration of estrogen-regulated gene expression.…”

Section: Introductionmentioning

confidence: 98%

“…Complete loss of ERa expression in ERa-negative mammary tumor cell lines has been linked to aberrant hypermethylation of a CpG island contained in its promoter (Ottaviano et al, 1994;Roodi et al, 1995). In recent years, epigenetic mechanisms of gene regulation have been increasingly associated with establishment and progression of cancer (Jones and Baylin, 2002;Momparler, 2003;Ting et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells

et al. 2008

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In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERa) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERa target genes silenced in ERa-negative mammary tumor cells. In cell lines derived from ERa-negative MDA-MB231 cells, stable expression of different levels of ERa from a transgene did not result in transcription of PR. A quantitative comparative analysis demonstrates that inhibiting DNA methyltransferases using 5-aza-2 0 -deoxycytidine or specific disruption of DNMT1 by small interfering RNAs and treatment with the histone-deacetylase inhibitor trichostatin A enabled ERa-mediated hormone-dependent expression of endogenous PR. We show that demethylation of a CpG island located in the first exon of PR was a prerequisite for ERa binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERa target genes involved in tumorigenesis. PR transcription did not subsist 4 days after removal of the DNA methyltransferase blocking agents, suggesting that hormone-induced expression of ERa target genes in ERa-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERa access to promoters.

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“…[1][2][3] This ER negativity is not the result of mutations in the coding region of the ER gene. 4 Thus, theoretically this negativity could be either the result of downregulation of ER expression in the tumour cells, or the result of the tumour being derived from cells which normally lack that expression. Normal basal, including myoepithelial, cells of the breast are ERnegative.…”

mentioning

confidence: 99%

Myoepithelial markers are expressed in at least 29% of oestrogen receptor negative invasive breast carcinoma

Kesse‐Adu

Shousha

2004

Modern Pathology

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Around 20% of invasive breast carcinoma are oestrogen receptor alpha (ER) negative. Theoretically, this negativity could be either due to the result of downregulation of ER expression in the tumour cells, or the result of the tumour being derived from or differentiating towards cells which normally lack that expression. Normal basal, including myoepithelial, cells of the breast are ERnegative. CD10, smooth muscle actin and S100 are markers of these basal cells that can be used for their demonstration in routinely processed sections. This study was aimed at comparing the incidence of positivity for three myoepithelial markers in ER-negative and ER-positive invasive breast carcinoma. We have examined sections of 117 cases of breast carcinoma, including 77 ER-negative and 40 ER-positive cases, for the expression of CD10, smooth muscle actin and S100, using the avidin-biotin complex immunoperoxidase technique. A tumour was considered positive if more than 10% of the tumour cells were positively stained. In all, 36 (47%) ER-negative tumours were positive for one or more of these myoepithelial markers. The percentage of positively stained tumour cells varied between 30 and 100%. Of the 40 ER-positive tumours, only three (8%) were positive; two for S100 and one for actin, with none being positive for CD10. If cases stained only with S100 are excluded, as some of these may represent luminal differentiation, definite myoepithelial differentiation seems to be present in 29% (22/77) of ER-negative tumours as compared with 2.5% (1/40) of ER-positive tumours; a difference which is highly significant (Po0.001). It is suggested that at least 29% of ER-negative invasive breast carcinomas may be derived from or differentiating along the direction of basal nonconventional luminal epithelial breast cells that normally lack the expression of ER but totally or partially express various myoepithelial markers. Such tumours might need a different therapeutic approach.

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Estrogen Receptor Gene Analysis in Estrogen Receptor-Positive and Receptor-Negative Primary Breast Cancer

Abstract: The correlation reported previously, as well as our current findings, suggest that further investigations are warranted to understand the possible linkage of the ER gene locus to hereditary breast cancer.

Cited by 230 publications

References 0 publications

Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion

Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion

Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells

Myoepithelial markers are expressed in at least 29% of oestrogen receptor negative invasive breast carcinoma

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