MicroRNAs are differentially deregulated in mammary malignant phyllodes tumour
Julia Y S Tsang
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Search for more papers by this authorYun-Bi Ni
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Search for more papers by this authorEnders KO Ng
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong
Search for more papers by this authorVivian Y Shin
Department of Surgery, The University of Hong Kong, Hong Kong
Search for more papers by this authorKo-Fung Mak
Department of Pathology, Alice Ho Miu Ling Nethersole Hospital, Hong Kong
Search for more papers by this authorEdna May L Go
Department of Pathology, University of the Philippines, Manila, Philippines
Search for more papers by this authorJohn Tawasil
Department of Pathology, University of the Philippines, Manila, Philippines
Search for more papers by this authorSiu-Ki Chan
Departments of Pathology, Kwong Wah Hospital, Hong Kong
Search for more papers by this authorChun-Wai Ko
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Search for more papers by this authorAva Kwong
Department of Surgery, The University of Hong Kong, Hong Kong
Search for more papers by this authorCorresponding Author
Gary M Tse
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Address for correspondence: G M Tse, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Ngan Shing Street, Shatin, Hong Kong. e-mail: [email protected]Search for more papers by this authorJulia Y S Tsang
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Search for more papers by this authorYun-Bi Ni
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Search for more papers by this authorEnders KO Ng
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong
Search for more papers by this authorVivian Y Shin
Department of Surgery, The University of Hong Kong, Hong Kong
Search for more papers by this authorKo-Fung Mak
Department of Pathology, Alice Ho Miu Ling Nethersole Hospital, Hong Kong
Search for more papers by this authorEdna May L Go
Department of Pathology, University of the Philippines, Manila, Philippines
Search for more papers by this authorJohn Tawasil
Department of Pathology, University of the Philippines, Manila, Philippines
Search for more papers by this authorSiu-Ki Chan
Departments of Pathology, Kwong Wah Hospital, Hong Kong
Search for more papers by this authorChun-Wai Ko
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Search for more papers by this authorAva Kwong
Department of Surgery, The University of Hong Kong, Hong Kong
Search for more papers by this authorCorresponding Author
Gary M Tse
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Address for correspondence: G M Tse, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Ngan Shing Street, Shatin, Hong Kong. e-mail: [email protected]Search for more papers by this authorAbstract
Aims
MicroRNAs (miRs) have been shown to play important roles in tumour progression. Their expression pattern can be useful for cancer classification. However, little is known about miRs in mammary phyllodes tumours (PT).
Methods and results
In this study, polymerase chain reaction (PCR)-based miR profiling was performed in a small PT cohort to identify deregulated miRs in malignant PT. The purported roles and targets of these miRs were further validated. Unsupervised clustering of miR expression profiling segregated PT into different grades, implicating the miR profile in PT classification. Among the deregulated miRs, miR-21, miR-335 and miR-155 were validated to be higher in malignant than in lower-grade PT in the independent cohort by quantitative PCR (qPCR) (P ≤ 0.032). Their expression correlated with some of the malignant histological features, including high stromal cellularity, nuclear pleomorphism and mitosis. Subsequent analysis of their downstream proteins, namely PTEN for miR-21/miR-155 and Rb for miR-335, also showed an independent significant negative association between miR and protein expression.
Conclusions
Differential expression of miRs in PT could be useful in diagnosis and grading of PT. Their deregulated expression, together with the altered downstream targets, implicated their active involvement in PT malignant transformation.
Supporting Information
| Filename | Description |
|---|---|
| his12648-sup-0001-TableS1-S3.docWord document, 68 KB | Table S1. Primer sequence for analysis of miR expression. Table S2. MiR showed differential expression between malignant and benign PTs in profiling analysis. Table S3. Multiple linear regression analysis with of RB and PTEN expression with miR and histopathological features. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Karim RZ, Scolyer RA, Tse GM, Tan PH, Putti TC, Lee CS. Pathogenic mechanisms in the initiation and progression of mammary phyllodes tumours. Pathology 2009; 41; 105–117.
- 2Tan PH, Jayabaskar T, Chuah KL et al. Phyllodes tumors of the breast: the role of pathologic parameters. Am. J. Clin. Pathol. 2005; 123; 529–540.
- 3Karim RZ, O'Toole SA, Scolyer RA et al. Recent insights into the molecular pathogenesis of mammary phyllodes tumours. J. Clin. Pathol. 2013; 66; 496–505.
- 4Tan WJ, Thike AA, Tan SY et al. CD117 expression in breast phyllodes tumors: a real phenomenon correlating with adverse pathologic parameters and reduced survival. Mod. Pathol. 2014; doi:10.1111/his.12648.
10.1111/his.12648 Google Scholar
- 5Ang MK, Ooi AS, Thike AA et al. Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression. Breast Cancer Res. Treat. 2011; 129; 319–329.
- 6Jones AM, Mitter R, Springall R et al. A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence. J. Pathol. 2008; 214; 533–544.
- 7Jones AM, Mitter R, Poulsom R et al. MRNA expression profiling of phyllodes tumours of the breast: identification of genes important in the development of borderline and malignant phyllodes tumours. J. Pathol. 2008; 216; 408–417.
- 8Heneghan HM, Miller N, Kerin MJ. MiRNAs as biomarkers and therapeutic targets in cancer. Curr. Opin. Pharmacol. 2010; 10; 543–550.
- 9Hayashita Y, Osada H, Tatematsu Y et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005; 65; 9628–9632.
- 10Lu J, Getz G, Miska EA et al. MicroRNA expression profiles classify human cancers. Nature 2005; 435; 834–838.
- 11Gong C, Nie Y, Qu S et al. MiR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors. Cancer Res. 2014; 74; 4341–4352.
- 12Yamanaka Y, Tagawa H, Takahashi N et al. Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia. Blood 2009; 114; 3265–3275.
- 13Scarola M, Schoeftner S, Schneider C, Benetti R. MiR-335 directly targets rb1 (prb/p105) in a proximal connection to p53-dependent stress response. Cancer Res. 2010; 70; 6925–6933.
- 14Muirhead DM, Hoffman HT, Robinson RA. Correlation of clinicopathological features with immunohistochemical expression of cell cycle regulatory proteins p16 and retinoblastoma: distinct association with keratinisation and differentiation in oral cavity squamous cell carcinoma. J. Clin. Pathol. 2006; 59; 711–715.
- 15Volinia S, Calin GA, Liu CG et al. A microrna expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 2006; 103; 2257–2261.
- 16Mattie MD, Benz CC, Bowers J et al. Optimized high-throughput microrna expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol. Cancer. 2006; 5; 24.
- 17Huang GL, Zhang XH, Guo GL et al. Clinical significance of miR-21 expression in breast cancer: Sybr-green I-based real-time RT–PCR study of invasive ductal carcinoma. Oncol. Rep. 2009; 21; 673–679.
- 18Moore LM, Zhang W. Targeting miR-21 in glioma: a small RNA with big potential. Exp. Opin. Ther. Targets 2010; 14; 1247–1257.
- 19Yan LX, Huang XF, Shao Q et al. MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. RNA 2008; 14; 2348–2360.
- 20Ribas J, Ni X, Castanares M et al. A novel source for miR-21 expression through the alternative polyadenylation of VMP1 gene transcripts. Nucleic Acids Res. 2012; 40; 6821–6833.
- 21Hatley ME, Patrick DM, Garcia MR et al. Modulation of K-ras-dependent lung tumorigenesis by microRNA-21. Cancer Cell 2010; 18; 282–293.
- 22Frezzetti D, De Menna M, Zoppoli P et al. Upregulation of miR-21 by ras in vivo and its role in tumor growth. Oncogene 2011; 30; 275–286.
- 23Greither T, Grochola LF, Udelnow A, Lautenschlager C, Wurl P, Taubert H. Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int. J. Cancer 2010; 126; 73–80.
- 24Yanaihara N, Caplen N, Bowman E et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 2006; 9; 189–198.
- 25Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J. Clin. Endocrinol. Metab. 2008; 93; 1600–1608.
- 26Iorio MV, Ferracin M, Liu CG et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005; 65; 7065–7070.
- 27Swann JB, Vesely MD, Silva A et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc. Natl Acad. Sci. USA 2008; 105; 652–656.
- 28Tavazoie SF, Alarcon C, Oskarsson T et al. Endogenous human micrornas that suppress breast cancer metastasis. Nature 2008; 451; 147–152.
- 29Gironella M, Seux M, Xie MJ et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc. Natl Acad. Sci. USA 2007; 104; 16170–16175.
- 30Tse GM, Putti TC, Kung FY et al. Increased p53 protein expression in malignant mammary phyllodes tumors. Mod. Pathol. 2002; 15; 734–740.
- 31Tse GM, Lui PC, Scolyer RA et al. Tumour angiogenesis and p53 protein expression in mammary phyllodes tumors. Mod. Pathol. 2003; 16; 1007–1013.
- 32Chen Z, Ma T, Huang C, Hu T, Li J. The pivotal role of microRNA-155 in the control of cancer. J. Cell. Physiol. 2014; 229; 545–550.
- 33Tse GM, Lui PC, Lee CS et al. Stromal expression of vascular endothelial growth factor correlates with tumor grade and microvessel density in mammary phyllodes tumors: a multicenter study of 185 cases. Hum. Pathol. 2004; 35; 1053–1057.
- 34Tsang JY, Mendoza P, Lam CC et al. Involvement of alpha- and beta-catenins and e-cadherin in the development of mammary phyllodes tumours. Histopathology 2012; 61; 667–674.
- 35Karim RZ, Gerega SK, Yang YH et al. Proteins from the WNT pathway are involved in the pathogenesis and progression of mammary phyllodes tumours. J. Clin. Pathol. 2009; 62; 1016–1020.
- 36Sawyer EJ, Hanby AM, Poulsom R et al. Beta-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breast. J. Pathol. 2003; 200; 627–632.
- 37Sawyer EJ, Poulsom R, Hunt FT et al. Malignant phyllodes tumours show stromal overexpression of c-myc and c-kit. J. Pathol. 2003; 200; 59–64.
- 38Cao J, Cai J, Huang D et al. MiR-335 represents an invasion suppressor gene in ovarian cancer by targeting Bcl-w. Oncol. Rep. 2013; 30; 701–706.
- 39Lynch J, Fay J, Meehan M et al. MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-beta signalling pathway. Carcinogenesis 2012; 33; 976–985.
- 40Png KJ, Yoshida M, Zhang XH et al. MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer. Genes Dev. 2011; 25; 226–231.
- 41Shu M, Zheng X, Wu S et al. Targeting oncogenic miR-335 inhibits growth and invasion of malignant astrocytoma cells. Mol. Cancer. 2011; 10; 59.
- 42Kedde M, Strasser MJ, Boldajipour B et al. RNA-binding protein DND1 inhibits microRNA access to target MRNA. Cell 2007; 131; 1273–1286.
- 43Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science 2007; 318; 1931–1934.
- 44Kuijper A, de Vos RA, Lagendijk JH, van der Wall E, van Diest PJ. Progressive deregulation of the cell cycle with higher tumor grade in the stroma of breast phyllodes tumors. Am. J. Clin. Pathol. 2005; 123; 690–698.
- 45Karim RZ, Gerega SK, Yang YH et al. P16 and prb immunohistochemical expression increases with increasing tumour grade in mammary phyllodes tumours. Histopathology 2010; 56; 868–875.
- 46Cimino-Mathews A, Hicks JL, Sharma R et al. A subset of malignant phyllodes tumors harbors alterations in the rb/p16 pathway. Hum. Pathol. 2013; 44; 2494–2500.
Citing Literature
