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Altered Expression of MLL Methyltransferase Family Genes in Breast Cancer

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Altered Expression of MLL Methyltransferase Family Genes in Breast Cancer INTERNATIONAL JOURNAL OF ONCOLOGY 43: 653-660, 2013 Altered expression of MLL methyltransferase family genes in breast cancer DORALINA DO AMARAL RABELLO1, CAROLINA AMARO DE MOURA1, ROSANGELA VIEIRA DE ANDRADE2, ANDREA BARRETTO MOTOYAMA1 and FABIO PITTELLA SILVA1 1Laboratory of Molecular Pathology of Cancer, Faculty of Health Sciences, University of Brasília, Brasília, DF 70.910-900; 2Laboratory of Genomic Sciences and Molecular Biotechnology, Catholic University of Brasília, Brasília, DF 70790-160, Brazil Received March 28, 2013; Accepted May 8, 2013 DOI: 10.3892/ijo.2013.1981 Abstract. The histone lysine methyltransferases contain a Introduction SET domain, which catalyzes the addition of methyl groups to specific lysine residues. The MLL family of genes encodes Breast cancer is the most frequent cancer and the most common histone-modifying enzymes with histone 3-lysine 4 methyl- cause of cancer-related death in women (1). In Brazil alone, transferase activity that can regulate gene transcription. The ~50,000 new cases of breast cancer are expected per year, with MLL family exists in multi-protein complexes and has been an estimated risk of 52 cases for every 100,000 women (2). implicated in a variety of processes including normal devel- Several studies have suggested that different genetic alterations opment and cell growth. Although some of the MLL family are linked to different histological types of breast cancer, such members have already been described to be involved in cancer, as estrogen receptor expression/lobular type, c-ErbB2 expres- a clear relationship of these genes with breast cancer is not sion/invasive type, among others (3,4). Recently, molecular determined to date. In the present study, we used quantitative studies have shown that breast cancer development involves PCR to investigate the expression profile of all fiveMLL genes not only alterations in oncogenes and tumor suppressor genes, [MLL (ALL-1), MLL2, MLL3, MLL4 and MLL5] in 7 breast but also epigenetic alterations in genes related to cellular cancer cell lines, 8 breast tumors and adjacent non-tumor growth, survival, motility and differentiation (5). Disturbance tissues and in 12 normal tissues. We observed a diminished of epigenetic regulation of gene expression through methyla- expression of all five genes in the breast cancer cell lines tion might contribute to tumorigenesis. In this context, altered when compared to normal breast tissue. We found a signifi- histone modifying enzymes such as methyltransferases may cantly decreased expression of MLL2 in the tumor samples play important roles in the process of carcinogenesis. compared to the non-tumor controls. In tumor samples, MLL5 The mixed lineage leukemia (MLL) family is character- also showed a clear suppression tendency. Among the normal ized by a conserved catalytic SET domain, responsible for tissues analyzed, all genes showed a markedly higher expres- the methyltransferase activity and comprises five genes sion in skeletal muscle and brain. Although further studies [MLL (ALL-1), MLL2, MLL3, MLL4 and MLL5]. are required to determine the exact role of these methyltrans- The mixed lineage leukemia gene (MLL or ALL-1, HRX ferases in cancer development, our results indicate that the and Htrx1) (Gene ID: 4297) is located in human chromo- suppression of MLL genes, especially MLL2 and 5, take part some 11q23 and is frequently involved in chromosomal in modulating breast carcinogenesis. Our assessment of the translocations in leukemia (6,7). MLL seems to function as a MLL family gene expression patterns in a diverse set of breast mammalian counterpart of Drosophila trx, which maintains cancer cell lines and in a multitude of tissue types and breast the expression of multiple Hox genes during development. tumors should lead to increasingly detailed information on the Mll-deficiency in mice results in failure to express Hox genes involvement of these genes in cancer progression. and in embryonic lethality. Heterozygosity for disrupted MLL, by homologous recombination in mouse embryonic stem cells, leads to retarded growth, hematopoietic abnormalities and skeleton malformations (8). Correspondence to: Professor Fábio Pittella Silva, Laboratory The MLL2 gene (Gene ID: 8085) is located on human of Molecular Pathology of Cancer, Faculty of Health Sciences, chromosome 12q13.12 and encodes a protein with domains University of Brasília, Campus Universitário Darcy Ribeiro, Asa similar to MLL. MLL2 was shown to be associated with Norte, Brasília, DF 70.910-900, Brazil Pax7 (paired-box transcription factor), forming the Wdr5- E-mail: [email protected] Ash2L-MLL2 histone methyltransferase (HMT) complex that directs tri-methylation of histone H3 lysine 4, when bound Key words: gene expression. MLL (ALL-1), MLL2, MLL3, MLL4 to Myf5. These chromatin modifications stimulate transcrip- and MLL5, breast cancer tional activation of target genes to regulate entry into the myogenic developmental program (9). Another study, based on 654 RABELLO et al: MLL METHYLTRANSFERASE EXPRESSION IN BREAST CANCER muscle-specific myogenin gene, suggested that transcriptional better understanding of the role of the MLL genes in breast activators Mef2d and Six4 mediate recruitment of trithorax carcinogenesis. group proteins Ash2L/MLL2 and UTX to MyoD-bound promoters to overcome the polycomb-mediated repression of Materials and methods muscle genes, allowing transcriptional activation of muscle- specific genes (10).MLL and MLL2 genes show highly similar Cell lines and culture. Seven breast cancer lines were used exon/intron structures. The proteins encoded by these genes on this study: HCC-1954, MCF-7, CAMA-1, SKBR-3, are ubiquitously expressed among adult human tissues and MDA-MB-231, MDA-MB-436 and MDA-MB-468. The cell although they share similar domains, they seem to act in a lines HCC-1954, MCF-7 and MDA-MB-231, obtained from different manner. MLL2 could not compensate for the hetero- the ATCC, were cultured in our laboratory in recommended zygosity of the disrupted MLL, by homologous recombination media and checked periodically for mycoplasma contamina- in mice (8), which indicates that their functions seem to be at tion. The main characteristics of the cell lines are summarized least partially non-overlapping. in Table I (20). Cells were grown in Dulbecco's modified MLL3 (Gene ID: 58508) maps to chromosome 7q36.1, a Eagle's medium (DMEM, Sigma-Aldrich, St. Louis, MO, USA) region usually deleted in hematological malignancies (11). supplemented with 10% fetal bovine serum (Sigma-Aldrich) MLL4 (Gene ID: 9757) is located on chromosome 19q13.1. and penicillin/streptomycin (100 U/ml; Life Technologies, MLL3 and MLL4 are found as part of a complex named Carlsbad, CA, USA) at 37˚C and 5% CO2. Total RNA from ASCOM (for ASC-2 COMplex), that acts as a p53 co-activator. these cells was extracted and used for expression analysis as This complex is required for the expression of endogenous described below. Additionally, total RNA from the remainder p53-target genes in response to the DNA damage (12). cells were kindly provided by the Ludwig Institute for Cancer Deletions or truncations in Mll, Mll2 and Mll3 in mice show Research, São Paulo, and were included in the gene expression different phenotypes, suggesting that MLL protein functions analysis. are not redundant (8,13). MLL5 (Gene ID: 55904) is located in human chromosome Normal tissues. A commercial panel (OriGene Technologies, 7q22.1. The nuclear protein encoded shows single PHD and Rockville, MD, USA) of total RNA from twelve human normal SET domains and lacks other conserved sequence elements, tissues from different organs (lung, small intestine (SI), brain, like its Drosophila homolog CG9007. MLL5 shows ubiqui- colon, kidney, muscle, liver, spleen, heart, testis, stomach and tous tissue expression and is highly conserved. It is the latest placenta) was used in this study. Total RNA of each normal addition to the mammalian Trithorax/MLL gene family and tissue was used to verify the expression levels of the genes recent studies show that the MLL5 may function in a different studied. manner, without methyltranferase activity, which is consistent with its different sequence of the SET domain compared to Tumor specimens. The sample collection protocol was the rest of the MLL family of H3K4 methyltransferases (14). It approved by the Research Ethics Committee of the Faculty was suggested that MLL5 would have an indirect mechanism of Health Sciences, University of Brasília, Brazil, based on regulating expression of histone-modifying enzymes, such as resolution 196/96 of the National Health Council/Brazilian LSD1 and SET7/9 (15). MLL5 was shown to promote myogenic Ministry of Health, project no. 025/09. Written informed differentiation through positive regulation of the pro-myogenic consent was obtained from all participants. The samples were genes Pax7, Myf5 and myogenin, which are impaired in MLL5 collected from surgically removed breast tissue from female knockdown, leading to serious differentiation defects (15). patients diagnosed with breast cancer at the Hospital of the Mll5 deficiency in mice leads to growth retardation, male University of Brasilia. A total of 14 samples (6 normal and infertility and defects in multiple hematopoietic lineages (16). 8 tumor samples) was used. The identification of tumor tissue Therefore, the defects found could be associated with deregu- from the removed samples was based on the histopathological lation of cell cycle control. examination and all types of breast cancer were included in our Some studies have shown that MLLs are critical analyses. Samples were selected based on tumor content (mini- co-activators in estrogen (E2)-dependent regulation of mally 80% tumor) as determined by microscopic pathological E2-responsive genes, through LXXLL motifs (NR boxes) analysis. A sample of normal tissue was collected from each (17,18). The suppression of MLL2 decreased expression of patient whenever possible. The clinical and histopathological estrogen receptor (ER) target genes (18). MLL3 and MLL4 characteristics of the patients are summarized in Table IV. coordinate with ERs and act in transcriptional regulation of HOXC10 in the presence of estrogen (19).
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