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Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.
French JD, Ghoussaini M, Edwards SL, Meyer KB, Michailidou K, Ahmed S, Khan S, Maranian MJ, O'Reilly M, Hillman KM, Betts JA, Carroll T, Bailey PJ, Dicks E, Beesley J, Tyrer J, Maia AT, Beck A, Knoblauch NW, Chen C, Kraft P, Barnes D, González-Neira A, Alonso MR, Herrero D, Tessier DC, Vincent D, Bacot F, Luccarini C, Baynes C, Conroy D, Dennis J, Bolla MK, Wang Q, Hopper JL, Southey MC, Schmidt MK, Broeks A, Verhoef S, Cornelissen S, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Loehberg CR, Ekici AB, Beckmann MW, Peto J, dos Santos Silva I, Johnson N, Aitken Z, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Zamora MP, Arias Perez JI, Benitez J, Anton-Culver H, Brenner H, Müller H, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Engel C, Brauch H, Hamann U, Justenhoven C, GENICA Network, Aaltonen K, Heikkilä P, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Sueta A, Bogdanova NV, Antonenkova NN, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, kConFab Investigators, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Peeters S, Smeets A, Floris G, Chang-Claude J, Rudolph A, Nickels S, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Sardella D, Couch FJ, Wang X, Pankratz VS, Lee A, Giles GG, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Ng CH, Vithana EN, Kristensen V, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devilee P, Seynaeve C, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Klevebring D, Schoof N, Hooning MJ, Martens JW, Collée JM, Tilanus-Linthorst M, Hall P, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cox A, Balasubramanian SP, Blot W, Signorello LB, Cai Q, Pharoah PD, Healey CS, Shah M, Pooley KA, Kang D, Yoo KY, Noh DY, Hartman M, Miao H, Sng JH, Sim X, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, McKay J, Toland AE, Ambrosone CB, Yannoukakos D, Godwin AK, Shen CY, Hsiung CN, Wu PE, Chen ST, Swerdlow A, Ashworth A, Orr N, Schoemaker MJ, Ponder BA, Nevanlinna H, Brown MA, Chenevix-Trench G, Easton DF, Dunning AM
(2013) Am J Hum Genet 92: 489-503
MeSH Terms: Binding Sites, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 11, Cyclin D1, Electrophoretic Mobility Shift Assay, Enhancer Elements, Genetic, Female, GATA3 Transcription Factor, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Silencer Elements, Transcriptional, ets-Domain Protein Elk-4
Show Abstract · Added March 10, 2014
Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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2 Members
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23 MeSH Terms
Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling.
Rai V, Touré F, Chitayat S, Pei R, Song F, Li Q, Zhang J, Rosario R, Ramasamy R, Chazin WJ, Schmidt AM
(2012) J Exp Med 209: 2339-50
MeSH Terms: Animals, Cell Line, Tumor, Cyclin D1, Female, Humans, Lysophospholipids, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle, Smooth, Vascular, Neoplasms, Proto-Oncogene Proteins c-akt, Rats, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Recombinant Proteins, Signal Transduction
Show Abstract · Added March 12, 2014
The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
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18 MeSH Terms
XZH-5 inhibits STAT3 phosphorylation and enhances the cytotoxicity of chemotherapeutic drugs in human breast and pancreatic cancer cells.
Liu A, Liu Y, Jin Z, Hu Q, Lin L, Jou D, Yang J, Xu Z, Wang H, Li C, Lin J
(2012) PLoS One 7: e46624
MeSH Terms: Animals, Apoptosis, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cyclin D1, Female, HeLa Cells, Histidine, Humans, Inhibitor of Apoptosis Proteins, Interleukin-6, Mice, Mice, SCID, Pancreatic Neoplasms, Phenylurea Compounds, Phosphorylation, Proto-Oncogene Proteins c-bcl-2, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor, STAT3 Transcription Factor, Survivin
Show Abstract · Added June 14, 2013
Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in breast and pancreatic cancer. Inhibiting constitutive STAT3 signaling represents a promising molecular target for therapeutic approach. Using structure-based design, we developed a non-peptide cell-permeable, small molecule, termed as XZH-5, which targeted STAT3 phosphorylation. XZH-5 was found to inhibit STAT3 phosphorylation (Tyr705) and induce apoptosis in human breast and pancreatic cancer cell lines expressing elevated levels of phosphorylated STAT3. XZH-5 could also inhibit interleukin-6-induced STAT3 phosphorylation in cancer cell lines expressing low phosphorylated STAT3. Inhibition of STAT3 signaling by XZH-5 was confirmed by the down-regulation of downstream targets of STAT3, such as Cyclin D1, Bcl-2, and Survivin at mRNA level. In addition, XZH-5 inhibited colony formation, cell migration, and enhanced the cytotoxicity of chemotherapeutic drugs when combined with Doxorubicin or Gemcitabine. Our results indicate that XZH-5 may be a potential therapeutic agent for breast and pancreatic cancers with constitutive STAT3 signaling.
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23 MeSH Terms
Cyclin D1 inactivation extends proliferation and alters histogenesis in the postnatal mouse retina.
Das G, Clark AM, Levine EM
(2012) Dev Dyn 241: 941-52
MeSH Terms: Animals, Cell Cycle, Cell Differentiation, Cell Proliferation, Cyclin D1, Cyclin D2, Cyclin D3, Mice, Mice, Knockout, Retina, Stem Cells
Show Abstract · Added November 2, 2015
BACKGROUND - The cell-cycle regulator Cyclin D1 is expressed in embryonic retinal progenitor cells (RPCs) and regulates their cell-cycle rate and neurogenic output. We report here that Cyclin D1 also has important functions in postnatal retinal histogenesis.
RESULTS - The initial production of Müller glia and bipolar cells was enhanced in Cyclin D1 knockout (Ccnd1(-/-) ) retinas. Despite a steeper than normal rate of depletion of the RPC population at embryonic ages, postnatal Ccnd1(-/-) retinas exhibited an extended window of proliferation, neurogenesis, and gliogenesis. Cyclin D3, normally confined to Müller glia, was prematurely expressed in Ccnd1(-/-) RPCs. However, Cyclin D3 did not compensate for Cyclin D1 in regulating cell-cycle kinetics or neurogenic output.
CONCLUSIONS - The data presented in this study along with our previous finding that Cyclin D2 was unable to completely compensate for the absence of Cyclin D1 indicate that Cyclin D1 regulates retinal histogenesis in ways not shared by the other D-cyclins.
Copyright © 2012 Wiley Periodicals, Inc.
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11 MeSH Terms
RAF265 inhibits the growth of advanced human melanoma tumors.
Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, Short SP, Sobolik T, Zaja-Milatovic S, Dahlman KB, Amiri KI, Jiang A, Lu P, Shyr Y, Stuart DD, Levy S, Sosman JA, Richmond A
(2012) Clin Cancer Res 18: 2184-98
MeSH Terms: Animals, Apoptosis, Base Sequence, Cell Cycle Proteins, Cell Proliferation, Cyclin D1, Extracellular Signal-Regulated MAP Kinases, Female, Gene Expression Profiling, Humans, Imidazoles, Ki-67 Antigen, MAP Kinase Signaling System, Male, Melanoma, Mice, Mice, Nude, Mutation, Oligonucleotide Array Sequence Analysis, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins p21(ras), Pyridines, Sequence Analysis, DNA, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, bcl-X Protein
Show Abstract · Added June 14, 2013
PURPOSE - The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.
EXPERIMENTAL DESIGN - Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated.
RESULTS - Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAF(V600E/K)), whereas eight of 17 (47%) tumors were BRAF wild type (BRAF(WT)). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAF(WT), of which 1 carried c-KIT(L576P) and another N-RAS(Q61R) mutation, while only 2 (29%) of the responding tumors were BRAF(V600E/K). Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11.
CONCLUSIONS - Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles.
©2012 AACR.
2 Communities
11 Members
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30 MeSH Terms
Mir-33 regulates cell proliferation and cell cycle progression.
Cirera-Salinas D, Pauta M, Allen RM, Salerno AG, Ramírez CM, Chamorro-Jorganes A, Wanschel AC, Lasuncion MA, Morales-Ruiz M, Suarez Y, Baldan Á, Esplugues E, Fernández-Hernando C
(2012) Cell Cycle 11: 922-33
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Cyclin-Dependent Kinase 6, G1 Phase Cell Cycle Checkpoints, HeLa Cells, Humans, Liver Regeneration, Male, Mice, Mice, Inbred C57BL, MicroRNAs, Oligonucleotides, Antisense, Phosphates
Show Abstract · Added February 12, 2016
Cholesterol metabolism is tightly regulated at the cellular level and is essential for cellular growth. microRNAs (miRNAs), a class of noncoding RNAs, have emerged as critical regulators of gene expression, acting predominantly at posttranscriptional level. Recent work from our group and others has shown that hsa-miR-33a and hsa-miR-33b, miRNAs located within intronic sequences of the Srebp genes, regulate cholesterol and fatty acid metabolism in concert with their host genes. Here, we show that hsa-miR-33 family members modulate the expression of genes involved in cell cycle regulation and cell proliferation. MiR-33 inhibits the expression of the cyclin-dependent kinase 6 (CDK6) and cyclin D1 (CCND1), thereby reducing cell proliferation and cell cycle progression. Overexpression of miR-33 induces a significant G 1 cell cycle arrest in Huh7 and A549 cell lines. Most importantly, inhibition of miR-33 expression using 2'fluoro/methoxyethyl-modified (2'F/MOE-modified) phosphorothioate backbone antisense oligonucleotides improves liver regeneration after partial hepatectomy (PH) in mice, suggesting an important role for miR-33 in regulating hepatocyte proliferation during liver regeneration. Altogether, these results suggest that Srebp/miR-33 locus may cooperate to regulate cell proliferation, cell cycle progression and may also be relevant to human liver regeneration.
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15 MeSH Terms
SLUG-induced elevation of D1 cyclin in breast cancer cells through the inhibition of its ubiquitination.
Mittal MK, Singh K, Misra S, Chaudhuri G
(2011) J Biol Chem 286: 469-79
MeSH Terms: Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Chromatin Assembly and Disassembly, Cyclin D1, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Neoplasm Invasiveness, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Snail Family Transcription Factors, Tamoxifen, Transcription Factors, Ubiquitin-Conjugating Enzymes, Ubiquitination
Show Abstract · Added July 10, 2015
UbcH5c, a member of the UbcH5 family of protein ubiquitin conjugase E2 enzymes, is a critical component of biological processes in human cells, being the initial ubiquitinating enzyme of substrates like IκB, TP53, and cyclin D1. We report here that the metastasis regulator protein SLUG inhibits the expression of UbcH5c directly through chromatin remodeling and thus, among other downstream effects, elevates the level of cyclin D1, thus enhancing the growth rates of breast cancer cells. Overexpression of SLUG in the SLUG-deficient breast cancer cells significantly decreased the levels of mRNA and protein of UbcH5c but only elevated the protein levels of cyclin D1. On the contrary, knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. Knockdown of UbcH5c in the SLUG-deficient human breast cells elevated the level of cyclin D1 as well as the rates of proliferation and invasiveness of these cells. Whereas the growth rates of the cells are enhanced due to overexpression of SLUG or knockdown of UbcH5c in the breast cancer cells tested, ER(+) cells also acquire resistance to the anti-estrogen 4-hydroxytamoxifen due to the rise of cyclin D1 levels in these cells. This study thus implicates high levels of SLUG and low levels of UbcH5c as a determinant in the progression of metastatic breast cancer.
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17 MeSH Terms
The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells.
Moss PE, Lyles BE, Stewart LV
(2010) Exp Cell Res 316: 3478-88
MeSH Terms: Androgen-Binding Protein, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Dihydrotestosterone, Gene Expression, Genes, Reporter, Humans, Hypoglycemic Agents, Male, Mutation, Neoplasms, Hormone-Dependent, PPAR gamma, Prostate-Specific Antigen, Prostatic Neoplasms, RNA, Small Interfering, Receptors, Androgen, Rosiglitazone, Thiazolidinediones, Transfection
Show Abstract · Added March 27, 2014
The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.
Copyright © 2010 Elsevier Inc. All rights reserved.
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20 MeSH Terms
t-DARPP regulates phosphatidylinositol-3-kinase-dependent cell growth in breast cancer.
Vangamudi B, Peng DF, Cai Q, El-Rifai W, Zheng W, Belkhiri A
(2010) Mol Cancer 9: 240
MeSH Terms: Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Survival, Chromones, Cyclin D1, Dopamine and cAMP-Regulated Phosphoprotein 32, Female, Humans, Immunoblotting, Immunohistochemistry, Morpholines, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Polymerase Chain Reaction, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, RNA, Small Interfering
Show Abstract · Added March 5, 2014
BACKGROUND - Recent reports have shown that t-DARPP (truncated isoform of DARPP-32) can mediate trastuzumab resistance in breast cancer cell models. In this study, we evaluated expression of t-DARPP in human primary breast tumors, and investigated the role of t-DARPP in regulating growth and proliferation in breast cancer cells.
RESULTS - Quantitative real time RT-PCR analysis using primers specific for t-DARPP demonstrated overexpression of t-DARPP in 36% of breast cancers (13/36) as opposed to absent to very low t-DARPP expression in normal breast tissue (p < 0.05). The mRNA overexpression of t-DARPP was overwhelmingly observed in ductal carcinomas, including invasive ductal carcinomas and intraductal carcinomas, rather than other types of breast cancers. The immunohistochemistry analysis of DARPP-32/t-DARPP protein(s) expression in breast cancer tissue microarray that contained 59 tumors and matched normal tissues when available indicated overexpression in 35.5% of primary breast tumors that were more frequent in invasive ductal carcinomas (43.7%; 21/48). In vitro studies showed that stable overexpression of t-DARPP in MCF-7 cells positively regulated proliferation and anchorage-dependent and -independent growth. Furthermore, this effect was concomitant with induction of phosphorylation of AKT(ser473) and its downstream target phospho(ser9) GSK3β, and increased Cyclin D1 and C-Myc protein levels. The knockdown of endogenous t-DARPP in HCC1569 cells led to a marked decrease in phosphorylation of AKTs(ser473) and GSK3β(ser9). The use of PI3K inhibitor LY294002 or Akt siRNA abrogated the t-DARPP-mediated phosphorylation of AKT(ser473) and led to a significant reduction in cell growth.
CONCLUSIONS - Our findings underscore the potential role of t-DARPP in regulating cell growth and proliferation through PI3 kinase-dependent mechanism.
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4 Members
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19 MeSH Terms
Cyclin D1b in human breast carcinoma and coexpression with cyclin D1a is associated with poor outcome.
Abramson VG, Troxel AB, Feldman M, Mies C, Wang Y, Sherman L, McNally S, Diehl A, Demichele A
(2010) Anticancer Res 30: 1279-85
MeSH Terms: Adult, Aged, Aged, 80 and over, Breast Neoplasms, Cohort Studies, Cyclin D1, Female, Follow-Up Studies, Humans, Immunohistochemistry, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Prognosis, Prospective Studies, Protein Isoforms, RNA, Messenger, Risk Factors
Show Abstract · Added March 27, 2014
BACKGROUND/AIM - Cyclin D1 is a mediator of cell-cycle control that is frequently overexpressed in primary ductal breast carcinomas, but its role is controversial. A polymorphism in the CCND1 gene, G870A, results in an aberrantly spliced protein (cyclin D1b) lacking the Thr-286 phosphorylation site necessary for nuclear export. Studies of murine fibroblasts have shown that although overexpression of canonical cyclin D1 (cyclin D1a) alone is not sufficient to drive malignant transformation, expression of nuclear cyclin D1b is oncogenic. Our objectives were to determine whether cyclin D1b is expressed in human breast carcinomas and to characterize the relationship of this protein to both cyclin D1a and clinical outcome in breast cancer patients.
PATIENTS AND METHODS - We performed a prospective cohort study of women with early-stage breast cancer and analyzed cyclin D1a and D1b expression in primary breast tumor sections. Expression was tested for correlation with other breast cancer prognostic factors and clinical outcome, including recurrence or death.
RESULTS - A total of 118 patients were included in this analysis, with a median follow-up of 44 months. Cyclin D1b was expressed in 26% of tumors and cyclin D1a was overexpressed in 27%; co-expression occurred in 4%. Cyclin D1a and/or D1b expression were not significantly associated with estrogen or progesterone receptor negativity, Her2 overexpression, young age, lymph node positivity, high tumor grade, nor large tumor size. The risk of recurrence was higher in those co-expressing D1a and D1b compared to the expression of either alone (relative risk=5.3, 95% confidence interval 1.27 to 22.1, p=0.02). The hazard ratio for those with co-expression compared with those without was 6.05 (p=0.04).
CONCLUSION - Expression of cyclin D1b occurs in primary human breast carcinomas and its coexpression with cyclin D1a may be a marker for increased recurrence risk, independently of other factors.
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18 MeSH Terms