Histone demethylase GASC1--a potential prognostic and predictive marker in invasive breast cancer

Bozena Berdel, Kaisa Nieminen, Ylermi Soini, Maria Tengström, Marjo Malinen, Veli-Matti Kosma, Jorma J Palvimo, Arto Mannermaa, Bozena Berdel, Kaisa Nieminen, Ylermi Soini, Maria Tengström, Marjo Malinen, Veli-Matti Kosma, Jorma J Palvimo, Arto Mannermaa

Abstract

Background: The histone demethylase GASC1 (JMJD2C) is an epigenetic factor suspected of involvement in development of different cancers, including breast cancer. It is thought to be overexpressed in the more aggressive breast cancer types based on mRNA expression studies on cell lines and meta analysis of human breast cancer sets. This study aimed to evaluate the prognostic and predictive value of GASC1 for women with invasive breast cancer.

Methods: All the 355 cases were selected from a cohort enrolled in the Kuopio Breast Cancer Project between April 1990 and December 1995. The expression of GASC1 was studied by immunohistochemistry (IHC) on tissue microarrays. Additionally relative GASC1 mRNA expression was measured from available 57 cases.

Results: In our material, 56% of the cases were GASC1 negative and 44% positive in IHC staining. Women with GASC1 negative tumors had two years shorter breast cancer specific survival and time to relapse than the women with GASC1 positive tumors (p=0.017 and p=0.034 respectively). The majority of GASC1 negative tumors were ductal cases (72%) of higher histological grade (84% of grade II and III altogether). When we evaluated estrogen receptor negative and progesterone receptor negative cases separately, there was 2 times more GASC1 negative than GASC1 positive tumors in each group (chi2, p= 0.033 and 0.001 respectively). In the HER2 positive cases, there was 3 times more GASC1 negative cases than GASC1 positives (chi2, p= 0.029). Patients treated with radiotherapy (n=206) and hormonal treatment (n=62) had better breast cancer specific survival, when they were GASC1 positive (Cox regression: HR=0.49, p=0.007 and HR=0.33, p=0.015, respectively). The expression of GASC1 mRNA was in agreement with the protein analysis.

Conclusions: This study indicates that the GASC1 is both a prognostic and a predictive factor for women with invasive breast cancer. GASC1 negativity is associated with tumors of more aggressive histopathological types (ductal type, grade II and III, ER negative, PR negative). Patients with GASC1 positive tumors have better breast cancer specific survival and respond better to radiotherapy and hormonal treatment.

Figures

Figure 1
Figure 1
Expression of GASC1 in invasive breast carcinoma of ductal type. (A) Positive immunostaining in nuclei of epithelial cells (arrows; immunoscores: 3 for the nuclear number and 3 for intensity of nuclear staining), positive staining visible in cytoplasm was not taken into account. Original magnification of x200. (B) Negative GASC1 immunostaining in nuclei of epithelial carcinoma cells. Original magnification of x200.
Figure 2
Figure 2
Breast cancer specific survival by Kaplan-Meier analysis. Overall, the patients with GASC1 immunopositive tumors have better survival than the patients with GASC1 negative tumors (p=0.017 Log Rank; p=0.012, Breslow; p=0.013, Tarone-Ware).
Figure 3
Figure 3
Breast cancer specific survival analysis by Cox regression. After adjusting the model to confound for the age at diagnosis, nodal status, size of tumor, and clinical stage, GASC1 positive patients have better survival than GASC1 negative. The p-value for the model is 0.000 and for the GASC1 status 0.001.
Figure 4
Figure 4
Time to relapse by Kaplan-Meier analysis. Overall, the patients with GASC1 immunopositive tumors have a longer time to relapse than the patients with GASC1 negative tumors (p=0.034, Log Rank; p=0.005, Breslow; p=0.010 Tarone-Ware).
Figure 5
Figure 5
Time to relapse analysis by Cox regression. GASC1 negative cases have a shorter time to relapse than GASC1 positive cases. The following covariates were included into the model: age at diagnosis, nodal status, size of tumor, clinical stage and GASC1 status. The p-value for the model is 0.000 and for the GASC1 status 0.002.
Figure 6
Figure 6
Breast cancer specific survival by Kaplan-Meier analysis. Overall, the patients with high expression of GASC1 mRNA in tumors have a better survival than patients with low GASC1 mRNA expression (p = 0.152, Log Rank).
Figure 7
Figure 7
Graph showing GASC1 mRNA expression in tumors of different histological grades. Boxes represent the 25–75th percentile; whiskers: range; black line: median; black dots: outliers. The highest GASC1 mRNA expression is detected in tumors of grade I (GR I; 0.761±0.099). Tumors of grade II (GR II; 0.510±0.070) and III (GR III; 0.510±0.069) show lower GASC1 mRNA expression than tumors of grade I. There is no difference in GASC1 mRNA expression between tumors of grade II and III. Kruskal-Wallis test, p=0.02. Mann–Whitney test: grade I versus II - p=0.006; grade I versus III - p=0.019, grade II versus III - p=0.821.
Figure 8
Figure 8
Graphs showing GASC1 mRNA expression according to progesterone receptor (PR) and HER2 status. (A) GASC1 mRNA relative level is lower in tumors showing negative or weak expression of PR (0.483±0.051) compared with tumors showing high PR expression (0.691±0.092; Mann–Whitney: p=0.016). (B) GASC1 mRNA relative level is higher in HER2 negative tumors (0.599±0.055) than in HER2 positive tumors (0.326±0.054; Mann–Whitney: p=0.004).

References

    1. Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20(8):1319–1329. doi: 10.1093/annonc/mdp322.
    1. Rodriguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17(3):330–339.
    1. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27–36. doi: 10.1093/carcin/bgp220.
    1. Stefanska B, Karlic H, Varga F, Fabianowska-Majewska K, Haslberger A. Epigenetic mechanisms in anti-cancer actions of bioactive food components - the implications in cancer prevention. Br J Pharmacol. 2012;167(2):279–297. doi: 10.1111/j.1476-5381.2012.02002.x.
    1. Van Neste L, Herman JG, Otto G, Bigley JW, Epstein JI, Van Criekinge W. The epigenetic promise for prostate cancer diagnosis. Prostate. 2012;72(11):1248–1261. doi: 10.1002/pros.22459.
    1. Chiam K, Centenera MM, Butler LM, Tilley WD, Bianco-Miotto T. GSTP1 DNA methylation and expression status is indicative of 5-aza-2’-deoxycytidine efficacy in human prostate cancer cells. PLoS One. 2011;6(9):e25634. doi: 10.1371/journal.pone.0025634.
    1. Gomori E, Pal J, Kovacs B, Doczi T. Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas. Diagn Pathol. 2012;7:8. doi: 10.1186/1746-1596-7-8.
    1. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–1068. doi: 10.1038/nbt.1685.
    1. Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T, Hansen KH, Helin K. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature. 2006;442(7100):307–311. doi: 10.1038/nature04837.
    1. Bannister AJ, Schneider R, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T. Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes. J Biol Chem. 2005;280(18):17732–17736.
    1. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001;410(6824):120–124. doi: 10.1038/35065138.
    1. Yang ZQ, Imoto I, Fukuda Y, Pimkhaokham A, Shimada Y, Imamura M, Sugano S, Nakamura Y, Inazawa J. Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines. Cancer Res. 2000;60(17):4735–4739.
    1. Liu G, Bollig-Fischer A, Kreike B, van de Vijver MJ, Abrams J, Ethier SP, Yang ZQ. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene. 2009;28(50):4491–4500. doi: 10.1038/onc.2009.297.
    1. Rui L, Emre NC, Kruhlak MJ, Chung HJ, Steidl C, Slack G, Wright GW, Lenz G, Ngo VN, Shaffer AL. et al.Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell. 2010;18(6):590–605. doi: 10.1016/j.ccr.2010.11.013.
    1. Wu J, Liu S, Liu G, Dombkowski A, Abrams J, Martin-Trevino R, Wicha MS, Ethier SP, Yang ZQ. Identification and functional analysis of 9p24 amplified genes in human breast cancer. Oncogene. 2012;31(3):333–341. doi: 10.1038/onc.2011.227.
    1. Wissmann M, Yin N, Muller JM, Greschik H, Fodor BD, Jenuwein T, Vogler C, Schneider R, Gunther T, Buettner R. et al.Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol. 2007;9(3):347–353. doi: 10.1038/ncb1546.
    1. Loh YH, Zhang W, Chen X, George J, Ng HH. Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev. 2007;21(20):2545–2557. doi: 10.1101/gad.1588207.
    1. Katoh Y, Katoh M. Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells. Int J Mol Med. 2007;20(2):269–273.
    1. Kauppinen JM, Kosma VM, Soini Y, Sironen R, Nissinen M, Nykopp TK, Karja V, Eskelinen M, Kataja V, Mannermaa A. ST14 gene variant and decreased matriptase protein expression predict poor breast cancer survival. Cancer Epidemiol Biomarkers Prev. 2010;19(9):2133–2142. doi: 10.1158/1055-9965.EPI-10-0418.
    1. Pellikainen MJ, Pekola TT, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM. p21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis. J Clin Pathol. 2003;56(3):214–220. doi: 10.1136/jcp.56.3.214.
    1. Hartikainen JM, Tuhkanen H, Kataja V, Dunning AM, Antoniou A, Smith P, Arffman A, Pirskanen M, Easton DF, Eskelinen M. et autosome-wide scan for linkage disequilibrium-based association in sporadic breast cancer cases in eastern Finland: three candidate regions found. Cancer Epidemiol Biomarkers Prev. 2005;14(1):75–80.
    1. Soini Y, Tuhkanen H, Sironen R, Virtanen I, Kataja V, Auvinen P, Mannermaa A, Kosma VM. Transcription factors zeb1, twist and snai1 in breast carcinoma. BMC Cancer. 2011;11:73. doi: 10.1186/1471-2407-11-73.
    1. Cancer TIAfRo. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. In: Tavassoéli FA, Devilee P, editor. IARC WHO Classification of Tumours. Lyon, France: IARCPress-WHO; 2003. p. 432.
    1. McNeill RE, Miller N, Kerin MJ. Evaluation and validation of candidate endogenous control genes for real-time quantitative PCR studies of breast cancer. BMC Mol Biol. 2007;8:107. doi: 10.1186/1471-2199-8-107.
    1. Chen Y, Guo Y, Ge X, Itoh H, Watanabe A, Fujiwara T, Kodama T, Aburatani H. Elevated expression and potential roles of human Sp5, a member of Sp transcription factor family, in human cancers. Biochem Biophys Res Commun. 2006;340(3):758–766. doi: 10.1016/j.bbrc.2005.12.068.
    1. Takahashi M, Nakamura Y, Obama K, Furukawa Y. Identification of SP5 as a downstream gene of the beta-catenin/Tcf pathway and its enhanced expression in human colon cancer. Int J Oncol. 2005;27(6):1483–1487.
    1. Khau T, Langenbach SY, Schuliga M, Harris T, Johnstone CN, Anderson RL, Stewart AG. Annexin-1 signals mitogen-stimulated breast tumor cell proliferation by activation of the formyl peptide receptors (FPRs) 1 and 2. FASEB J. 2011;25(2):483–496. doi: 10.1096/fj.09-154096.
    1. Yom CK, Han W, Kim SW, Kim HS, Shin HC, Chang JN, Koo M, Noh DY, Moon BI. Clinical significance of annexin A1 expression in breast cancer. J Breast Cancer. 2011;14(4):262–268. doi: 10.4048/jbc.2011.14.4.262.
    1. Gebeshuber CA, Martinez J. miR-100 suppresses IGF2 and inhibits breast tumorigenesis by interfering with proliferation and survival signaling. Oncogene. 2012.
    1. Yang F, Bi J, Xue X, Zheng L, Zhi K, Hua J, Fang G. Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J. 2012;279(17):3159–3165. doi: 10.1111/j.1742-4658.2012.08694.x.
    1. Amit D, Hochberg A. Development of targeted therapy for a broad spectrum of cancers (pancreatic cancer, ovarian cancer, glioblastoma and HCC) mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences. Int J Clin Exp Med. 2012;5(4):296–305.
    1. Qiu J, Yang R, Rao Y, Du Y, Kalembo FW. Risk factors for breast cancer and expression of insulin-like growth factor-2 (IGF-2) in women with breast cancer in Wuhan City. China. PLoS One. 2012;7(5):e36497. doi: 10.1371/journal.pone.0036497.
    1. Qiao Y, Jiang X, Lee ST, Karuturi RK, Hooi SC, Yu Q. FOXQ1 regulates epithelial-mesenchymal transition in human cancers. Cancer Res. 2011;71(8):3076–3086. doi: 10.1158/0008-5472.CAN-10-2787.
    1. Zhang H, Meng F, Liu G, Zhang B, Zhu J, Wu F, Ethier SP, Miller F, Wu G. Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis. Cancer Res. 2011;71(4):1292–1301. doi: 10.1158/0008-5472.CAN-10-2825.
    1. Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M. et al.Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006;125(3):467–481. doi: 10.1016/j.cell.2006.03.028.
    1. Hoffmann I, Roatsch M, Schmitt ML, Carlino L, Pippel M, Sippl W, Jung M. The role of histone demethylases in cancer therapy. Mol Oncol. 2012.
    1. Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007;25(1):1–14. doi: 10.1016/j.molcel.2006.12.010.
    1. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823–837. doi: 10.1016/j.cell.2007.05.009.
    1. Peters AH, Kubicek S, Mechtler K, O’Sullivan RJ, Derijck AA, Perez-Burgos L, Kohlmaier A, Opravil S, Tachibana M, Shinkai Y. et al.Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol Cell. 2003;12(6):1577–1589. doi: 10.1016/S1097-2765(03)00477-5.
    1. De Koning L, Savignoni A, Boumendil C, Rehman H, Asselain B, Sastre-Garau X, Almouzni G. Heterochromatin protein 1alpha: a hallmark of cell proliferation relevant to clinical oncology. EMBO Mol Med. 2009;1(3):178–191. doi: 10.1002/emmm.200900022.
    1. Dong C, Wu Y, Wang Y, Wang C, Kang T, Rychahou PG, Chi YI, Evers BM, Zhou BP. Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene. 2012.
    1. Tang D, Xu S, Zhang Q, Zhao W. The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer. Med Oncol. 2012;29(2):526–33. doi: 10.1007/s12032-011-9948-2.
    1. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. Mod Pathol. 2011;24(7):924–931. doi: 10.1038/modpathol.2011.54.
    1. Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, Marotti JD, Hankinson SE, Colditz GA, Tamimi RM. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17(7):1867–1874. doi: 10.1158/1078-0432.CCR-10-2021.
    1. Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol. 2010;23(2):205–212. doi: 10.1038/modpathol.2009.159.
    1. Wang Y, Romigh T, He X, Tan MH, Orloff MS, Silverman RH, Heston WD, Eng C. Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. Oncogene. 2011;30(42):4327–4338. doi: 10.1038/onc.2011.144.
    1. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36(Suppl 1):59–72.
    1. Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think. J Exp Med. 2011;208(10):1931–1935. doi: 10.1084/jem.20111855.
    1. Dumont AG, Yang Y, Reynoso D, Katz D, Trent JC, Hughes DP. Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors. Carcinogenesis. 2012;33(9):1674–1683. doi: 10.1093/carcin/bgs221.
    1. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A. et al.Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14(5):518–527. doi: 10.1038/nm1764.
    1. Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, van de Vijver MJ. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007;9(5):R65. doi: 10.1186/bcr1771.

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