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Functional Evidence for a Novel Human Breast Carcinoma Metastasis Suppressor, BRMS1, Encoded at Chromosome 11Q131

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Functional Evidence for a Novel Human Breast Carcinoma Metastasis Suppressor, BRMS1, Encoded at Chromosome 11Q131 [CANCER RESEARCH 60, 2764–2769, June 1, 2000] Advances in Brief Functional Evidence for a Novel Human Breast Carcinoma Metastasis Suppressor, BRMS1, Encoded at Chromosome 11q131 M. Jabed Seraj,2,3 Rajeev S. Samant,2 Michael F. Verderame, and Danny R. Welch4 Jake Gittlen Cancer Research Institute [M. J. S., R. S. S., D. R. W.] and Department of Medicine [M. F. V.], The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033-2390 Abstract Two general approaches were used to identify these metastasis- controlling genes. The first involved comparison of gene expression in We previously showed that introduction of a normal, neomycin-tagged poorly or nonmetastatic cells with matched metastasis-competent human chromosome 11 reduces the metastatic capacity of MDA-MB-435 cells. The second took advantage of clinical observations that identi- (435) human breast carcinoma cells by 70–90% without affecting tumor- igenicity, suggesting the presence of one or more metastasis suppressor fied nonrandom chromosomal changes that occur during tumor pro- genes encoded on human chromosome 11. To identify the gene(s) respon- gression. This information localized the gene(s) from which cloning sible, differential display comparing chromosome 11-containing (neo11/ could commence. In this study, we combined aspects of both strate- 435) and parental, metastatic cells was done. We describe the isolation and gies to identify a novel, functional breast carcinoma metastasis sup- functional characterization of a full-length cDNA for one of the novel pressor gene. genes, designated breast-cancer metastasis suppressor 1 (BRMS1), which A recent cataloging of differential gene/protein gene expression and maps to human chromosome 11q13.1-q13.2. Stably transfected MDA-MB- chromosomal abnormalities occurring as breast carcinoma acquires 435 and MDA-MB-231 breast carcinoma cells still form progressively metastatic potential (2) revealed that some karyotypic changes com- growing, locally invasive tumors when injected into mammary fat pads monly occur in early-stage breast cancer (8p, 13q, 16q, 17p, 17q, and but are significantly less metastatic to lungs and regional lymph nodes. These data provide compelling functional evidence that breast-cancer 19p), whereas others typically occur later in breast cancer progression metastasis suppressor 1 is a novel mediator of metastasis suppression in (1p, 1q, 3p, 6q, 7q, 11p, and 11q). Among the most common changes human breast carcinoma. in both familial or sporadic breast carcinoma are losses of genetic material on chromosome 11q, which occurs in 40–65% of cases. INTRODUCTION There are several regions spanning the q-arm of chromosome 11 for which associations have been made with breast cancer progression. When breast carcinoma cells are confined to breast tissue, long- Among the most common are amplifications and deletions involving term survival rates are high. But when tumor cells disseminate to and regions near band 11q13. Within this region, there is evidence sup- colonize secondary sites, cure rates drop significantly. Likewise, porting the existence of a number of critical genes, including tumor- quality of life for patients with stage IV (metastatic) disease is promoting, tumor-suppressing, metastasis-promoting and metastasis- significantly worse than for those with stage I (local) carcinoma. suppressing genes. The genes int-2, hst, bcl-1, glutathione Thus, decreased morbidity and mortality will depend on prevention S-transferase, CCND1, and EMS-1, which map to 11q13, are ampli- and/or effective treatment of metastatic disease. To that end, under- fied in breast cancer at a frequency between 3 and 20%. There exists standing the biological, biochemical, and genetic mechanisms under- a high-frequency involvement of rat chromosome 1 (which is syntenic pinning tumor cell invasion and metastasis will be required. to human chromosome 11) in the development and progression of rat Metastasis-regulatory genes can be broadly categorized as either mammary tumors (3). Therefore, based on these observations and metastasis-promoting or metastasis-suppressing. Analogous to the high-frequency deletions involving 11q13-q14 in late-stage, meta- role of oncogenes in tumorigenesis, metastasis promoters drive con- version from nonmetastatic to metastatic. Although similar in other static breast carcinomas, we tested the hypothesis that chromosome respects, metastasis suppressors are distinguishable from tumor sup- 11q encodes a metastasis suppressor gene. Upon finding that intro- pressors in that the former block only metastasis when introduced into duction of a normal human chromosome 11 into metastatic MDA- metastatic tumor cells (i.e., not tumorigenicity). As expected, tumor MB-435 (435) human breast carcinoma suppressed metastasis without suppressors suppress both phenotypes because tumorigenicity is a affecting tumorigenicity (4), we set out to identify the gene(s) respon- prerequisite to metastasis (1). To date, only six metastasis suppressor sible. We report here the isolation and functional characterization of genes (Nm23, KISS1, Kai1, E-cadherin, MKK4, TIMPs) have been a metastasis suppressor gene from this region. shown to functionally suppress metastasis using in vivo models (re- viewed in Ref. 2). MATERIALS AND METHODS Received 2/4/00; accepted 4/18/00. Cell Lines and Cell Culture. MDA-MB-435 and MDA-MB-231 are hu- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with man estrogen receptor- and progesterone receptor-negative cell lines derived 18 U.S.C. Section 1734 solely to indicate this fact. from metastatic (pleural effusion), infiltrating ductal breast carcinoma. Both 1 This research was supported by Grant DAMD-96-1-6152 (to D. R. W.) from the cell lines form progressively growing tumors when injected into the mammary United States Army Medical Research and Material Command with additional support fat pads of immunocompromised mice. MDA-MB-435 cells develop macro- from the NIH (Grant CA-62168), the National Foundation for Cancer Research, and the Jake Gittlen Memorial Golf Tournament. scopic metastases in the lungs and regional lymph nodes by 10–12 weeks 2 Contributed equally to this work. postinoculation, but rarely metastasize after direct injection into the lateral tail 3 Present address: Department of Urology, University of Virginia, Charlottesville, VA vein. The opposite pattern exists for 231 in athymic mice. MDA-MB-435 cell 22908. clones into which a normal, neomycin-tagged human chromosome 11 had been 4 To whom requests for reprints should be addressed, at Jake Gittlen Cancer Research Institute, Mailstop H059, Room C7810, The Pennsylvania State University College of introduced by microcell-mediated transfer (designated neo11/435) are sup- Medicine, 500 University Drive, Hershey, PA 17033-2390. pressed at least 75% for metastasis from the mammary fat pad (4). 2764 Downloaded from cancerres.aacrjournals.org on October 6, 2021. © 2000 American Association for Cancer Research. BRMS1, A CANCER METASTASIS SUPPRESSOR GENE BRMS15 transfectants were derived after transfection of full-length BRMS1 F5A3 and 8A3 were provisional nomenclature used during the initial part of cDNA (see below) cloned into the constitutive mammalian expression vector, these studies. pcDNA3 (Invitrogen, San Diego, CA). All cell lines were cultured in a 1Ϻ1 Chromosomal Localization of BRMS1. BRMS1 cDNA was used to (v/v) mixture of DMEM and Ham’s F-12 medium supplemented with 5% fetal screen bacterial artificial chromosome and P1 artificial chromosome libraries bovine serum (Atlanta Biologicals, Atlanta, GA), 1% nonessential amino at Genome Systems, Inc. (St. Louis, MO). Bacterial artificial chromosome acids, and 1.0 mM sodium pyruvate, but no antibiotics or antimycotics. Trans- clones 412(n24) and 536(h18) harbored BRMS1 as confirmed by direct se- fected cells and neo11/435 hybrids also received 500 ␮g/ml Geneticin (G-418; quencing.6 The genomic sequence was determined using the 412(n24 clone). Life Technologies, Inc., Gaithersburg, MD). BRMS1-transfected 435 cells DNA was isolated and labeled with digoxigenin dUTP by nick translation and acquired an unexplained acute sensitivity to trypsin; therefore, cultures were combined with sheared human DNA before hybridization to metaphase chro- thereafter passaged using 2 mM EDTA solution in calcium- and magnesium- mosomes derived from phytohemagglutinin-stimulated peripheral blood leu- free Dulbecco’s PBS. Hybrid clones and transfectants were used before pas- kocytes in a solution containing 50% formamide, 10% dextran sulfate, and 2ϫ sage 11 in all cases to minimize the impacts of clonal diversification and SSC. Specific hybridization signals were detected by exposing the hybrid cell phenotypic instability. For all functional and biological assays, cells between lines to antidigoxigenin antibodies followed by counterstaining with DAPI. 70 and 90% confluence were used with viability Ͼ95%. All lines were Specific labeling was seen along the proximal long arm of a group C chro- routinely checked and found to be negative for Mycoplasma spp. contamina- mosome, which was subsequently confirmed to be chromosome 11 based on tion using the GenProbe method (Fisher Scientific, Pittsburgh, PA). cohybridization with genomic probes known to map to 11p15 and 11cen. Cell line nomenclature was developed to identify the origin and nature of Measurements of 71 of 80 specifically
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