Mutations of the Estrogen Receptor in Endometrial Carcinoma: Evidence of an Association with High Tumor Grade

Assikis, Vasilios J.; Bilimoria, Malcolm M.; Muenzner, Henry D.; Lurain, John R.; Jordan, V. Craig

doi:10.1006/gyno.1996.0305

Cited by 17 publications

(5 citation statements)

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“…Similarly, mRNA splice variants lacking one or more of exons 5–8, encoding the hormone-binding domain, have been described in normal 35 36 37 38 and malignant 22 23 35 36 37 39 breast as well as in normal 22 40 41 42 43 44 45 and malignant 42 43 44 45 46 endometrial tissue. Point mutations of the ligand binding domain encoding sequence of ESR1 have also been described to occur in both breast and endometrial cancers 25 26 27 30 47 48 .…”

Section: Discussionmentioning

confidence: 99%

Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

Holst

Høivik

Gibson

et al. 2016

Sci Rep

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The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be effective in endometrial cancer. Recently it has been shown that hormone-binding domain alterations of ERα in breast cancer contribute to acquired resistance to anti-estrogen therapy. In analyses of genomic data from The Cancer Genome Atlas (TCGA), we observe that endometrial carcinomas manifest recurrent ESR1 gene amplifications that truncate the hormone-binding domain encoding region of ESR1 and are associated with reduced mRNA expression of exons encoding the hormone-binding domain. These findings support a role for hormone-binding alterations of ERα in primary endometrial cancer, with potentially important therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

Holst

Høivik

Gibson

et al. 2016

Sci Rep

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show abstract

“…These mutations do not alter the protein sequence, so they would not be predicted to significantly affect ER function. In fact, the majority of polymorphisms identified do not have an observable phenotype associated with them, regardless of the tissue of origin (263,271,287). Although the ER␣ codon 10 polymorphism has been found in numerous normal and diseased tissues, it is not commonly associated with the diseased state (221,283,288,289).…”

Section: Er␣ Y537n/y537smentioning

confidence: 99%

Estrogen Receptor Mutations in Human Disease

2004

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As early as the 1800s, the actions of estrogen have been implicated in the development and progression of breast cancer. The estrogen receptor (ER) was identified in the late 1950s and purified a few years later. However, it was not until the 1980s that the first ER was molecularly cloned, and in the mid 1990s, a second ER was cloned. These two related receptors are now called ERalpha and ERbeta, respectively. Since their discovery, much research has focused on identifying alterations within the coding sequence of these receptors in clinical samples. As a result, a large number of naturally occurring splice variants of both ERalpha and ERbeta have been identified in normal epithelium and diseased or cancerous tissues. In contrast, only a few point mutations have been identified in human patient samples from a variety of disease states, including breast cancer, endometrial cancer, and psychiatric diseases. To elucidate the mechanism of action for these variant isoforms or mutant receptors, experimental mutagenesis has been used to analyze the function of distinct amino acid residues in the ERs. This review will focus on ERalpha and ERbeta alterations in breast cancer.

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“…However, results from breast and endometrial cancer studies have identified reduction in ER expression, presence of dominant-negative ER variants, mutational inactivation of ER, and abnormal expression of coactivators/repressors of ER as probable causes for this phenomenon (30)(31)(32)(33)(34). ER␣ mutations are rare but have been reported in metastatic and tamoxifen-resistant malignancies of the breast (32,33) and of the endometrium (34). Nevertheless, ER␣ mutations have not been reported in ovarian cancer specimens.…”

Section: Fig 2 Sequence Analyses Of the Wild-type Er␣ Transcript (Ementioning

confidence: 99%

Expression of human estrogen receptor-α and -β, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells

Lau

Mok

1999

Proc. Natl. Acad. Sci. U.S.A.

256

161

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Our understanding of the roles played by sex hormones in ovarian carcinogenesis has been limited by a lack of data concerning the mode of sex hormone action in human ovarian surface epithelial (HOSE) cells, the tissue of origin of >90% of ovarian cancers. We have compared the relative abundance of estrogen receptor (ER)␣, ER␤, progesterone receptor (PR), and androgen receptor (AR) mRNA in four primary cultures of HOSE cells obtained from postmenopausal women to those found in late serous adenocarcinoma primary cell cultures and established ovarian cancer cell lines. We observed coexpression of ER␣ and ER␤ mRNA along with AR and PR transcripts in normal HOSE cells and disruption of ER␣ mRNA expression as well as dramatic down-regulation of PR and AR transcript expression in most ovarian cancer cells. In contrast, levels of ER␤ mRNA were unaffected by the malignant state. Additionally, a novel mutation involving a 32-bp deletion in exon 1 of ER␣ transcripts was detected in the SKOV3 cell line. This mutation would explain why SKOV3 was reported to be ER-positive but estrogen-insensitive. Taken together, these findings suggest that estrogens, signaling via either or both ER subtypes, may play an indispensable role in regulating normal HOSE cell functions. Therefore, loss of ER␣, PR, and AR mRNA expression in HOSE cells may be responsible for neoplastic transformation in this cell type. In contrast, the roles played by ER␤ in normal and malignant HOSE cells remain elusive. Finally, the coexistence of mutated ER␣ mRNA and normal ER␤ transcripts in SKOV3 argues in favor of a dependency of ER␤ action on functional ER␣s.

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Mutations of the Estrogen Receptor in Endometrial Carcinoma: Evidence of an Association with High Tumor Grade

Cited by 17 publications

References 0 publications

Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

Estrogen Receptor Mutations in Human Disease

Expression of human estrogen receptor-α and -β, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells

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