Mapping an Endometrial Cancer Tumor Suppressor Gene at 10q25 and Development of a Bacterial Clone Contig for the Consensus Deletion Interval

Peiffer-Schneider, Stacia; Noonan, Ferrin C; Mutch, David G.; Simpkins, Sally B.; Herzog, Thomas J.; Rader, Janet S.; Elbendary, Alaa; Gersell, Deborah J.; Call, Katherine M.; Goodfellow, Paul J.

doi:10.1006/geno.1998.5399

Cited by 25 publications

(23 citation statements)

References 28 publications

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“…52 The EMX2 suppresses endometrial epithelial proliferation 53,54 and is a candidate tumor suppressor gene based on its location within a consensus region of allelic loss in uterine endometrial adenocarcinoma. 55 BZA/E2 was the only TSEC that significantly increased EMX2 gene expression when comparison to E2 alone, thus demonstrating an antiproliferative effect of this TSEC. The effects on EMX2 suggest that, among those tested, BZA may be the optimal SERM for use in a TSEC, inducing the antiproliferative and tumor-suppressing effects of EMX2.…”

Section: Discussionmentioning

confidence: 89%

Tissue Selective Estrogen Complexes (TSECs) Differentially Modulate Markers of Proliferation and Differentiation in Endometrial Cells

et al. 2013

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Selective estrogen receptor modulators (SERMs) have tissue-specific estrogen receptor (ER) modulating properties. Combining an SERM with one or more estrogens to form a tissue selective estrogen complex (TSEC) can provide an improved blend of tissue-specific ER agonist and antagonist effects. While both estrogens and SERMs affect the uterine endometrium, not all TSECs reverse the endometrial effects of estrogens preventing endometrial proliferation and hyperplasia. Their action in uterine cells is not completely understood. HOXA 10, leukemia inhibitory factor (LIF), progesterone receptor (PR), and EMX2 are genes known to regulate endometrial proliferation and differentiation. The expression of these genes was used to assess endometrial effects of SERMs and TSECs. We evaluated the effects of raloxifene (RAL), tamoxifen (TAM), lasofoxifene (LAS), bazedoxifene acetate (BZA), and progesterone (P) alone and in combination with estradiol (E2) in Ishikawa cells. Increased HOXA10, LIF, PR, and EMX2 messenger RNA (mRNA) expression was noted in E2-treated cells compared with vehicle-treated controls. All TSECs maintained E2-induced PR expression and all except TAM prevented estrogen-induced LIF expression. The TSEC containing BZA uniquely decreased HOXA10 expression and increased EMX2 expression. The TSECs alter endometrial cell proliferation by selective modulation of estrogen responsive genes, maintaining the antiproliferative effects mediated by PR and inhibiting LIF. The differential effect of TSECs on endometrial gene expression suggests a mechanism by which they manifest differential effects on endometrial safety against the risk of estrogen-induced endometrial hyperplasia.

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Section: Discussionmentioning

confidence: 89%

Tissue Selective Estrogen Complexes (TSECs) Differentially Modulate Markers of Proliferation and Differentiation in Endometrial Cells

et al. 2013

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“…Human SUFU is widely expressed in fetal and adult tissues; it maps to 10q24-q25, a region which is deleted in glioblastoma, prostate cancer, malignant melanoma, and endometrial cancer [Gray et al, 1995;Rasheed et al, 1995;Albarosa et al, 1996;Peiffer-Schneider et al, 1998;Stone et al, 1999]. Taylor et al [2002] reported a subset of children with medulloblastoma and SUFU mutations, both germline and somatic, accompanied by loss of heterozygosity of the wildtype allele.…”

Section: Suppressor Of Fused (Sufu)mentioning

confidence: 98%

The hedgehog signaling network

Cohen

2003

American J of Med Genetics Pt A

387

230

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In the hedgehog signaling network, mutations result in various phenotypes, including, among others, holoprosencephaly, nevoid basal cell carcinoma syndrome, Pallister-Hall syndrome, Greig cephalopolysyndactyly, Rubinstein-Taybi syndrome, isolated basal cell carcinoma, and medulloblastoma. Active Hedgehog ligand is double lipid modified with a C-terminal cholesterol moiety and an N-terminal palmitate. Transport active Hedgehog from the signaling cell to the responding cell occurs through three mechanisms: 1). formation of multimeric Hedgehog which makes it soluble; 2). function of Dispatched in releasing the lipid-anchored protein from the signaling cell; and 3). movement across the plasma membrane of the responding cell by Tout-velu-dependent synthesis of heparan sulfate proteoglycan. In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling. Patched and Smoothened may shuttle oppositely between the plasma membrane and endocytic vesicles in response to active Hedgehog ligand. In downstream signaling, Cubitus interruptus (Gli proteins in vertebrates), Costal 2, Fused, and Suppressor of Fused form a tetrameric complex. Cubitus interruptus is a bifunctional transcription regulator. In the absence of active Hedgehog ligand, a truncated transcriptional repressor is generated that binds target genes and blocks their transcription. In the presence of active Hedgehog ligand, a full length transcriptional activator binds target genes and upregulates their transcription. Target genes include Wingless (Wnt gene family in vertebrates), Decapentaplegic (Bone Morphogenetic Proteins in vertebrates), and Patched. The upregulation of Patched expression, resulting in Patched protein at the cell membrane, sequesters Hedgehog and limits its spread beyond the cells in which it is produced. Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. Many more factors that are essential for the hedgehog signaling network are also discussed: Megalin, Rab23, Hip, GAS1, PKA, GSK3, CK1, Slimb, SAP18, and CBP.

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“…23 In addition to the 10q23 region (which PTEN tumor suppressor gene has been mapped to), 2,3 more distal regions of LOH (at 10q25-q26) have been identified and correlated to endometrial tumorigenesis. 24,25 Deletion mapping studies indicated that at least two minimal consensus regions of allelic loss exist at this location: between D10S587 and D10S1723 26 and between D10S221 and D10S610 loci 27 To further address questions on the role of the 10q25-q26 region in endometrial carcinoma, we screened 94 sporadic EC cases from Sardinia, where the population is genetically homogeneous and already demonstrated to be helpful in defining the molecular basis of complex diseases like cancer. 28 Frequency of EC in Sardinia has been reported similar to that of other Western countries, with 18.7 new cases per 100,000 inhabitants.…”

mentioning

confidence: 99%

Microsatellite analysis at 10q25-q26 in Sardinian patients with sporadic endometrial carcinoma

Palmieri

Manca²,

Cossu

et al. 2000

Cancer

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Mapping an Endometrial Cancer Tumor Suppressor Gene at 10q25 and Development of a Bacterial Clone Contig for the Consensus Deletion Interval

Cited by 25 publications

References 28 publications

Tissue Selective Estrogen Complexes (TSECs) Differentially Modulate Markers of Proliferation and Differentiation in Endometrial Cells

Tissue Selective Estrogen Complexes (TSECs) Differentially Modulate Markers of Proliferation and Differentiation in Endometrial Cells

The hedgehog signaling network

Microsatellite analysis at 10q25-q26 in Sardinian patients with sporadic endometrial carcinoma

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