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Advances in Brief [CANCER RESEARCH 62, 1289–1295, March 1, 2002] Advances in Brief Stanniocalcin 2 Is an Estrogen-responsive Gene Coexpressed with the Estrogen Receptor in Human Breast Cancer1 Toula Bouras,2 Melissa C. Southey, Andy C. Chang, Roger R. Reddel, Dorian Willhite, Richard Glynne, Michael A. Henderson, Jane E. Armes, and Deon J. Venter Cancer Functional Genomics Unit, Murdoch Children’s Research Institute, 10th Floor Royal Children’s Hospital, Parkville, Victoria 3052, Australia [T. B., D. J. V.]; Department of Pathology, The University of Melbourne, Victoria 3010, Australia [M. C. S., J. E. A., D. J. V.]; Molecular Pathology Laboratory, Victorian Breast Cancer Research Consortium, Australia [J. E. A.]; Department of Surgery, St Vincent’s Hospital, Fitzroy, Victoria 3065, Australia [M. A. H.]; Children’s Medical Research Institute, Westmead, Sydney, NSW 2145, Australia [A. C. C., R. R. R.]; and Eos Biotechnology, South San Francisco, California 94080 [D. W., R. G.] Abstract believed to include genetic or epigenetic aberrations occurring at the level of ER signaling. Differences in gene expression are likely to explain the phenotypic Recent cDNA microarray analyses have identified widespread dif- variation between hormone-responsive and hormone-unresponsive breast ferences in gene expression between ER-positive and ER-negative cancers. In this study, DNA microarray analysis of ϳ10,000 known genes and 25,000 expressed sequence tag clusters was performed to identify breast cancer clinical samples. Specifically, in two independent stud- genes induced by estrogen and repressed by the pure antiestrogen ICI 182 ies representing a total of 83 breast carcinomas, the clustering of 780 in vitro that correlated with estrogen receptor (ER) expression in global gene expression patterns divided tumors into two major groups primary breast carcinomas in vivo. Stanniocalcin (STC) 2 was identified as distinguished by ER status (3, 4). As yet, no systematic analysis has one of the genes that fulfilled these criteria. DNA microarray hybridiza- been described to unify the observed changes and determine which tion showed a 3-fold induction of STC2 mRNA expression in MCF-7 cells genes represent novel estrogen-responsive genes. We undertook a < in 3 h of estrogen exposure and a 3-fold repression in the presence of comprehensive analysis of genes responsive to estrogen and the pure antiestrogen (one-way ANOVA, P < 0.0005). In 13 ER-positive and 12 antiestrogen ICI 182 780 in the well-studied, ER-positive breast ER-negative breast carcinomas, the microarray-derived mRNA levels observed for STC2 correlated with tumor ER mRNA (Pearson’s correla- cancer cell line model, MCF-7 (5), using a high-density Affymetrix ϳ P < 0.0001) and ER protein status (Spearman’s rank array capable of measuring 35,000 genes and expressed sequence ;0.85 ؍ tion, r P < 0.0001). The expression profile of STC2 was tag clusters. To further pinpoint estrogen target genes with potential ;0.73 ؍ correlation, r further confirmed by in situ hybridization and immunohistochemistry on clinical relevance, these in vitro data were combined with the expres- a larger cohort of 236 unselected breast carcinomas using tissue microar- sion profiles of a cohort of 13 ER-positive and 12 ER-negative rays. STC2 mRNA and protein expression were found to be associated primary breast carcinomas, and the results were evaluated on an with tumor ER status (Fisher’s exact test, P < 0.005). The related gene, independent panel of 236 clinical breast cancer samples. Using this STC1, was also examined and shown to be associated with ER status in approach, STC2, a homologue of a glycoprotein hormone originally breast carcinomas (Fisher’s exact test, P < 0.05). This study demonstrates the feasibility of using global gene expression data derived from an in vitro found to regulate calcium/phosphate homeostasis in bony fish (6), was model to pinpoint novel estrogen-responsive genes of potential clinical identified as an estrogen-responsive gene that was also differentially relevance. expressed between ER-positive and ER-negative breast carcinomas. Introduction Materials and Methods 3 The amount of ER protein in breast tumors is frequently used to Human Breast Cell Lines. MCF-7 cells obtained from the American Type group breast cancer patients in a clinical setting, both as a prognostic 4 Culture Collection were cultured at 37°C in 5% CO2 in RPMI 1640 supple- indicator and in predicting the likelihood of response to treatment with mented with 10% FCS (Sigma Chemical Co., Castle Hill, New South Wales, antiestrogens, such as tamoxifen (1). Additional patient information is Australia) to 25% confluence. The cells were then washed three times with gained from tumor levels of PR protein, as the gene for the PR is PBS to remove residual serum and grown for 24 h in phenol red-free RPMI up-regulated in response to estrogen and, thus, used as a surrogate 1640 supplemented with 10% charcoal-stripped FCS (Sigma Chemical Co.). marker of ER activity (2). A current difficulty with the hormonal Cells were then treated with 100 nM 17␤ estradiol or vehicle (ethanol) for management of breast cancer patients is the diversity observed in the periods of 30 min to 48 h before mRNA was harvested. In parallel, for the clinic beyond that predicted by the measurement of steroid receptor antiestrogen experiments, cells were grown to 25% confluence in complete protein levels in tumor tissue. The molecular basis of the differences RPMI 1640 supplemented with 10% FCS. Cells were then washed three times with PBS and serum starved for another 24 h in phenol red-free RPMI. Serum in clinical behavior observed between ER-positive and ER-negative was then readded for another 24 h in phenol red-free RPMI 1640, and cells breast carcinomas and the failure to respond to antiestrogen therapy is were treated with 50 nM of the antiestrogen ICI 182 780 (AstraZeneca Phar- maceutical LP, Wilmington, DE) or vehicle (ethanol) for periods between 30 Received 10/2/01; accepted 1/18/02. min and 48 h. Cells were lysed, and mRNA was isolated using TRIzol reagent The costs of publication of this article were defrayed in part by the payment of page (Life Technologies, Inc.) as specified by the manufacturer. All experiments charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. were replicated independently three times. In parallel to mRNA extractions, 1 Supported by the University of Melbourne, the Peter MacCallum Cancer Institute, the ability of estrogen to induce cell proliferation and ICI 182 780 to arrest cell and the Victorian Breast Cancer Research Consortium. growth was verified by fluorescence-activated cell sorting analysis of pro- 2 To whom requests for reprints should be addressed, at Cancer Functional Genomics Unit, Murdoch Children’s Research Institute, 10th Floor, Royal Children’s Hospital, pidium iodide-stained cells. mRNA was also extracted from five actively Parkville, Victoria 3052, Australia. Phone: 61-3-8341-6231; Fax: 61-3-9348-1391; E- growing (in the presence of serum) breast cancer cell lines, two ER positive mail: [email protected]. (MCF-7 and BT-474) and three ER negative (MDA-MB-231/453/435). 3 The abbreviations used are: ER, estrogen receptor; ERE, estrogen-response element; HRE, hormone response element; PR, progesterone receptor; DIG, digoxigenin; STC, stanniocalcin. 4 Internet address: http://www.atcc.org. 1289 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2002 American Association for Cancer Research. STANNIOCALCIN 2 IN BREAST CANCER Tumor Specimens. mRNA was extracted from a total of 25 archival fresh of SSC (ϫ2, ϫ1, and ϫ0.1) for 15 min. To digest, unbound probe sections frozen breast carcinomas obtained from patients undergoing surgery at the were treated with RNase A (final concentration: 20 ␮g/ml) for 1 h at 37°C, Peter MacCallum Cancer Institute. A pathologist grossly dissected histologi- followed by two washes in PBS. Slides were then incubated in blocking cally verified tumor tissue from normal adjacent tissue. All mRNA was solution [Roche Blocking Reagent 1% (w/v) in buffer 1, 100 mM maleic acid, extracted by the standard guanidinium thiocyanate methodology. The ER and 150 mM NaCl (pH 7.5)] for 30 min. Blocking solution (100 ␮l) containing protein status of the tumors was determined clinically by immunohistochem- 0.75 units/ml Anti-DIG[Fab]-AP (Roche Diagnostics Australia Pty. Ltd.) was Ն istry. Tumors were deemed ER positive if 10% of cells stained at an intensity added to each section, coverslipped, and incubated for1hatroom temperature. of weak or above. Of the 25 tumors, 13 were classified as ER positive and 12 Probe localization was visualized by adding nitroblue tetrazolium/5-bromo-4- ER negative. Of the 13 ER-positive cases, 6 were weakly staining, 5 moder- chloro-3-indolyl phosphate (Roche Diagnostics Australia Pty. Ltd.) color rea- ately, and 2 strongly. Appropriate institutional approval was obtained for all gent, according to the manufacturer’s instructions. Sections were then rinsed in tumor material used in this study. water to stop color development, counterstained with 0.1% methyl-green, and Microarray Hybridization. Oligonucleotide arrays (Eos Biotechnology- mounted using Kaiser’s glycerol gelatin (Merck, Whitehouse Station, NJ). specified Affymetrix 43K GeneChip Set) composed of 10,000 human genes Scoring of in Situ Hybridization. Each arrayed tissue sample was probed and 25,000 human expressed sequence tag clusters were used for hybridiza- tion. The protocols used for poly(A)ϩ mRNA purification, cDNA synthesis, in with a sense and antisense probe for STC1 and STC2. Staining of normal vitro transcription, chip hybridization, and statistical analysis are described by human endometrium with STC1/STC2 probes served as a positive and internal Glynne et al. (7). negative tissue control.
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