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Specific genes expressed in association with progesterone receptors in meningioma.

ABSTRACT: An association between hormones and meningioma has been postulated. No data exist that examine gene expression in meningioma by hormone receptor status. The data are surgical specimens from 31 meningioma patients undergoing neurosurgical resection at Brigham and Women's Hospital from March 15, 2004 to May 10, 2005. Progesterone and estrogen hormone receptors (PR and ER, respectively) were measured via immunohistochemistry and compared with gene expression profiling results. The sample is 77% female with a mean age of 55.7 years. Eighty percent were grade 1 and the mean MIB was 6.2, whereas 33% and 84% were ER+ and PR+, respectively. Gene expression seemed more strongly associated with PR status than with ER status. Genes on the long arm of chromosome 22 and near the neurofibromatosis type 2 (NF2) gene (22q12) were most frequently noted to have expression variation, with significant up-regulation in PR+ versus PR- lesions, suggesting a higher rate of 22q loss in PR- lesions. Pathway analyses indicated that genes in collagen and extracellular matrix pathways were most likely to be differentially expressed by PR status. These data, although preliminary, are the first to examine gene expression for meningioma cases by hormone receptor status and indicate a stronger association with PR than with ER status. PR status is related to the expression of genes near the NF2 gene, mutations in which have been identified as the initial event in many meningiomas. These findings suggest that PR status may be a clinical marker for genetic subgroups of meningioma and warrant further examination in a larger data set.

SUBMITTER: Claus EB

PROVIDER: S-EPMC3256746 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Specific genes expressed in association with progesterone receptors in meningioma.

Claus Elizabeth B EB Park Peter J PJ Carroll Rona R Chan Jennifer J Black Peter M PM

Cancer research 20080101 1

An association between hormones and meningioma has been postulated. No data exist that examine gene expression in meningioma by hormone receptor status. The data are surgical specimens from 31 meningioma patients undergoing neurosurgical resection at Brigham and Women's Hospital from March 15, 2004 to May 10, 2005. Progesterone and estrogen hormone receptors (PR and ER, respectively) were measured via immunohistochemistry and compared with gene expression profiling results. The sample is 77% fem ...[more]

PMID: 18172325

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Project description:BackgroundEstrogen and progesterone are potent breast mitogens. In addition to steroid hormones, multiple signaling pathways input to estrogen receptor (ER) and progesterone receptor (PR) actions via posttranslational events. Protein kinases commonly activated in breast cancers phosphorylate steroid hormone receptors (SRs) and profoundly impact their activities.MethodsTo better understand the role of modified PRs in breast cancer, we measured total and phospho-Ser294 PRs in 209 human breast tumors represented on 2754 individual tissue spots within a tissue microarray and assayed the regulation of this site in human tumor explants cultured ex vivo. To complement this analysis, we assayed PR target gene regulation in T47D luminal breast cancer models following treatment with progestin (promegestone; R5020) and antiprogestins (mifepristone, onapristone, or aglepristone) in conditions under which the receptor is regulated by Lys388 SUMOylation (K388 intact) or is SUMO-deficient (via K388R mutation to mimic persistent Ser294 phosphorylation). Selected phospho-PR-driven target genes were validated by qRT-PCR and following RUNX2 shRNA knockdown in breast cancer cell lines. Primary and secondary mammosphere assays were performed to implicate phospho-Ser294 PRs, epidermal growth factor signaling, and RUNX2 in breast cancer stem cell biology.ResultsPhospho-Ser294 PR species were abundant in a majority (54%) of luminal breast tumors, and PR promoter selectivity was exquisitely sensitive to posttranslational modifications. Phospho-PR expression and target gene programs were significantly associated with invasive lobular carcinoma (ILC). Consistent with our finding that activated phospho-PRs undergo rapid ligand-dependent turnover, unique phospho-PR gene signatures were most prevalent in breast tumors clinically designated as PR-low to PR-null (luminal B) and included gene sets associated with cancer stem cell biology (HER2, PAX2, AHR, AR, RUNX). Validation studies demonstrated a requirement for RUNX2 in the regulation of selected phospho-PR target genes (SLC37A2). In vitro mammosphere formation assays support a role for phospho-Ser294-PRs via growth factor (EGF) signaling as well as RUNX2 as potent drivers of breast cancer stem cell fate.ConclusionsWe conclude that PR Ser294 phosphorylation is a common event in breast cancer progression that is required to maintain breast cancer stem cell fate, in part via cooperation with growth factor-initiated signaling pathways and key phospho-PR target genes including SLC37A2 and RUNX2. Clinical measurement of phosphorylated PRs should be considered a useful marker of breast tumor stem cell potential. Alternatively, unique phospho-PR target gene sets may provide useful tools with which to identify patients likely to respond to selective PR modulators that block PR Ser294 phosphorylation as part of rational combination (i.e., with antiestrogens) endocrine therapies designed to durably block breast cancer recurrence.

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Specific genes expressed in association with progesterone receptors in meningioma.

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Specific genes expressed in association with progesterone receptors in meningioma.

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