Abstract
Despite their similar histomorphologic appearance, adenoid cystic carcinomas of the breast and salivary glands (bACCs and sACCs, respectively) are clinically and pathologically diverse. We studied the expression levels of 18 microRNAs (miRNAs) in bACCs and sACCs and control normal breast and salivary gland tissues (bNs and sNs, respectively) by quantitative real-time polymerase chain reaction on formalin-fixed paraffin embedded tissues. miRNAs showing significant differences between the study groups were selected for target prediction. Increased expression of miR-17 and miR-20a was found in bACCs compared with bNs (p miR-17 = 0.017 and p miR-20a = 0.024, respectively), while the expression level of let-7b and miR-193b was lower in sACCs compared with normal sNs (p let-7b = 0.032 and p miR-193b = 0.023, respectively). Expression of miR-23b and miR-27b differed between normal breast and normal salivary gland tissue (p miR-23b = 0.007 and p miR-27b = 0.024, respectively), but not between bACCs and sACCs. The potential target mRNAs CCND1 and BCL2 were identified as reported targets of let-7b, miR-193b, miR-17, and miR-20a. Expression of their corresponding proteins cyclin D1 and Bcl-2 was studied by immunohistochemistry. We found both proteins overexpressed in bACCs as well as sACCs in comparison with corresponding normal tissues. However, expression of cyclin D1 and Bcl-2 proteins was not significantly different between bACCs and sACCs or between bNs and sNs. Although no differences in miRNA levels were found between bACCs and sACCs, in both organs, miRNA expression level was highly different between tumor tissue and control tissue.
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References
Ambros V (2001) microRNAs: tiny regulators with great potential. Cell 107:823–826
Anderson JN Jr, Beenken SW, Crowe R, Soong SJ, Peters G, Maddox WA, Urist MM (1995) Prognostic factors in minor salivary gland cancer. Head Neck 17:480–486
Azoulay S, Lae M, Freneaux P, Merle S, Al Ghuzlan A, Chnecker C, Rosty C, Klijanienko J, Sigal-Zafrani B, Salmon R, Fourquet A, Sastre-Garau X, Vincent-Salomon A (2005) KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. Mod Pathol Off J US Can Acad Pathol Inc 18:1623–1631. doi:10.1038/modpathol.3800483
Calvano Filho CM, Calvano-Mendes DC, Carvalho KC, Maciel GA, Ricci MD, Torres AP, Filassi JR, Baracat EC (2014) Triple-negative and luminal A breast tumors: differential expression of miR-18a-5p, miR-17-5p, and miR-20a-5p. Tumour Biol J Int Soc Oncodev Biol Med 35:7733–7741. doi:10.1007/s13277-014-2025-7
Carthew RW (2006) Gene regulation by microRNAs. Curr Opin Genet Dev 16:203–208. doi:10.1016/j.gde.2006.02.012
Chang CC, Yang YJ, Li YJ, Chen ST, Lin BR, Wu TS, Lin SK, Kuo MY, Tan CT (2013) MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma. Oral Oncol 49:923–931. doi:10.1016/j.oraloncology.2013.03.430
Ciccolallo L, Licitra L, Cantu G, Gatta G, Group EW (2009) Survival from salivary glands adenoid cystic carcinoma in European populations. Oral Oncol 669–674
Crisi GM, Marconi SA, Makari-Judson G, Goulart RA (2005) Expression of c-kit in adenoid cystic carcinoma of the breast. Am J Clin Pathol 124:733–739. doi:10.1309/61MV-ENEK-5EJ7-JKGF
Dweep H, Sticht C, Pandey P, Gretz N (2011) miRWalk--database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform 44:839–847. doi:10.1016/j.jbi.2011.05.002
Edwards PC, Bhuiya T, Kelsch RD (2003) C-kit expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and monomorphic adenoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 95:586–593. doi:10.1067/moe.2003.31
Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer Nature reviews. Cancer 6:259–269. doi:10.1038/nrc1840
Ettl T, Schwarz S, Kleinsasser N, Hartmann A, Reichert TE, Driemel O (2008) Overexpression of EGFR and absence of C-KIT expression correlate with poor prognosis in salivary gland carcinomas. Histopathology 53:567–577. doi:10.1111/j.1365-2559.2008.03159.x
Ghabach B, Anderson WF, Curtis RE, Huycke MM, Lavigne JA, Dores GM (2010) Adenoid cystic carcinoma of the breast in the United States (1977 to 2006): a population-based cohort study. Breast Cancer Res BCR 12:R54. doi:10.1186/bcr2613
Haddad R, Colevas AD, Krane JF, Cooper D, Glisson B, Amrein PC, Weeks L, Costello R, Posner M (2003) Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study. Oral Oncol 39:724–727
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833. doi:10.1038/nature03552
Holst VA, Marshall CE, Moskaluk CA, Frierson HF Jr (1999) KIT protein expression and analysis of c-kit gene mutation in adenoid cystic carcinoma. Mod Pathol Off J US Can Acad Pathol Inc 12:956–960
Hotte SJ, Winquist EW, Lamont E, MacKenzie M, Vokes E, Chen EX, Brown S, Pond GR, Murgo A, Siu LL (2005) Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands expressing c-kit: a Princess Margaret Hospital phase II consortium study. J Clin Oncol Off J Am Soc Clin Oncol 23:585–590. doi:10.1200/jco.2005.06.125
Hsu SD, Tseng YT, Shrestha S, Lin YL, Khaleel A, Chou CH, Chu CF, Huang HY, Lin CM, Ho SY, Jian TY, Lin FM, Chang TH, Weng SL, Liao KW, Liao IE, Liu CC, Huang HD (2014) miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions. Nucleic Acids Res 42:D78–D85. doi:10.1093/nar/gkt1266
Jeng YM, Lin CY, Hsu HC (2000) Expression of the c-kit protein is associated with certain subtypes of salivary gland carcinoma. Cancer Lett 154:107–111
Jiang LC, Huang SY, Zhang DS, Zhang SH, Li WG, Zheng PH, Chen ZW (2014) Expression of beclin 1 in primary salivary adenoid cystic carcinoma and its relation to Bcl-2 and p53 and prognosis Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica … [et al.] 47:252–258. doi: 10.1590/1414-431X20133231
Kiss O, Tokes AM, Spisak S, Szilagyi A, Lippai N, Szekely B, Szasz AM, Kulka J (2014) Breast- and salivary gland-derived adenoid cystic carcinomas: potential post-transcriptional divergencies. A pilot study based on miRNA expression profiling of four cases and review of the potential relevance of the findings. Pathol Oncol Res POR. doi:10.1007/s12253-014-9770-1
Kleer CG, Oberman HA (1998) Adenoid cystic carcinoma of the breast: value of histologic grading and proliferative activity. Am J Surg Pathol 22:569–575
Liu L, Hu Y, Fu J, Yang X, Zhang Z (2013) MicroRNA155 in the growth and invasion of salivary adenoid cystic carcinoma. J Oral Pathol Med Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol 42:140–147. doi:10.1111/j.1600-0714.2012.01189.x
Mastropasqua MG, Maiorano E, Pruneri G, Orvieto E, Mazzarol G, Vento AR, Viale G (2005) Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast. Mod Pathol Off J US Can Acad Pathol Inc 18:1277–1282. doi:10.1038/modpathol.3800423
Mattick JS, Makunin IV (2005) Small regulatory RNAs in mammals human molecular genetics 14 Spec No 1:R121-132. doi: 10.1093/hmg/ddi101
Mc LP, Tennant R, Sarokhan J (1953) Adenoid cystic carcinoma of the breast; report of a case with unusual features. Surgery 33:905–908
Milano A, Longo F, Basile M, Iaffaioli RV, Caponigro F (2007) Recent advances in the treatment of salivary gland cancers: emphasis on molecular targeted therapy. Oral Oncol 43:729–734. doi:10.1016/j.oraloncology.2006.12.012
Mitani Y, Roberts DB, Fatani H, Weber RS, Kies MS, Lippman SM, El-Naggar AK (2013) MicroRNA profiling of salivary adenoid cystic carcinoma: association of miR-17-92 upregulation with poor outcome. PLoS One 8:e66778. doi:10.1371/journal.pone.0066778
Nkanza NK (1988) Adenoid cystic carcinoma of the prostate. Cent Afr J Med 34:166–168
Norberg-Spaak L, Dardick I, Ledin T (2000) Adenoid cystic carcinoma: use of cell proliferation, BCL-2 expression, histologic grade, and clinical stage as predictors of clinical outcome. Head Neck 22:489–497
Nordkvist A, Mark J, Gustafsson H, Bang G, Stenman G (1994) Non-random chromosome rearrangements in adenoid cystic carcinoma of the salivary glands. Genes Chromosom Cancer 10:115–121
Onitilo AA, Engel JM, Greenlee RT, Mukesh BN (2009) Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res 7:4–13. doi:10.3121/cmr.2009.825
Paulino AF, Huvos AG (1999) Epithelial tumors of the lacrimal glands: a clinicopathologic study. Ann Diagn Pathol 3:199–204. doi:10.1053/ADPA00300199
Persson M, Andren Y, Mark J, Horlings HM, Persson F, Stenman G (2009) Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci U S A 106:18740–18744. doi:10.1073/pnas.0909114106
Pfeffer MR, Talmi Y, Catane R, Symon Z, Yosepovitch A, Levitt M (2007) A phase II study of imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands. Oral Oncol 43:33–36. doi:10.1016/j.oraloncology.2005.12.026
Reis-Filho JS, Savage K, Lambros MB, James M, Steele D, Jones RL, Dowsett M (2006) Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Mod Pathol Off J US Can Acad Pathol Inc 19:999–1009. doi:10.1038/modpathol.3800621
Renehan A, Gleave EN, Hancock BD, Smith P, McGurk M (1996) Long-term follow-up of over 1000 patients with salivary gland tumours treated in a single centre. Br J Surg 83:1750–1754
Sakurai M, Miki Y, Masuda M, Hata S, Shibahara Y, Hirakawa H, Suzuki T, Sasano H (2012) LIN28: a regulator of tumor-suppressing activity of let-7 microRNA in human breast cancer. J Steroid Biochem Mol Biol 131:101–106. doi:10.1016/j.jsbmb.2011.10.007
Sequeiros-Santiago G, Garcia-Carracedo D, Fresno MF, Suarez C, Rodrigo JP, Gonzalez MV (2009) Oncogene amplification pattern in adenoid cystic carcinoma of the salivary glands. Oncol Rep 21:1215–1222
Sequeiros Santiago G, Rodrigo Tapia JP, Garcia-Carracedo D, Garcia Pedrero J, Suarez Nieto C, Gonzalez Meana MV (2004) CCND1 gene amplification in the adenoid cystic carcinoma of the minor salivary glands. Acta Otorrinolaringol Esp 55:88–92
Stefani M, Speranza N (1970) A case of cylindroma of the vagina. Riv Anat Patol Oncol 36:77–105
Strianese D, Baldi G, Staibano S, Baldi A, De Rosa G, Tranfa F, Bonavolonta G (2007) Expression of apoptosis-related markers in malignant epithelial tumours of the lacrimal gland and their relation to clinical outcome. Br J Ophthalmol 91:1239–1243. doi:10.1136/bjo.2007.118661
Sun X, Fan C, Du N, Ren H (2013) Possible carcinogenesis of tumor suppressor let-7. Med Hypotheses 81:410–413. doi:10.1016/j.mehy.2013.05.033
Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756. doi:10.1158/0008-5472.can-04-0637
Tao J, Wu D, Li P, Xu B, Lu Q, Zhang W (2012) microRNA-18a, a member of the oncogenic miR-17-92 cluster, targets Dicer and suppresses cell proliferation in bladder cancer T24 cells. Mol Med Rep 5:167–172. doi:10.3892/mmr.2011.591
Tchertkoff V, Sedlis A (1962) Cylindroma of the cervix. Am J Obstet Gynecol 84:749–752
Vattemi E, Graiff C, Sava T, Pedersini R, Caldara A, Mandara M (2008) Systemic therapies for recurrent and/or metastatic salivary gland cancers. Expert Rev Anticancer Ther 8:393–402. doi:10.1586/14737140.8.3.393
Venkitaraman R (2010) Triple-negative/basal-like breast cancer: clinical, pathologic and molecular features. Expert Rev Anticancer Ther 10:199–207. doi:10.1586/era.09.189
Vered M, Braunstein E, Buchner A (2002) Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin. Head Neck 24:632–636. doi:10.1002/hed.10104
Visone R, Croce CM (2009) MiRNAs and cancer. Am J Pathol 174:1131–1138. doi:10.2353/ajpath.2009.080794
Vranic S, Bender R, Palazzo J, Gatalica Z (2013) A review of adenoid cystic carcinoma of the breast with emphasis on its molecular and genetic characteristics. Hum Pathol 44:301–309. doi:10.1016/j.humpath.2012.01.002
Vranic S, Bilalovic N, Lee LM, Kruslin B, Lilleberg SL, Gatalica Z (2007) PIK3CA and PTEN mutations in adenoid cystic carcinoma of the breast metastatic to kidney. Hum Pathol 38:1425–1431. doi:10.1016/j.humpath.2007.03.021
Vranic S, Frkovic-Grazio S, Lamovec J, Serdarevic F, Gurjeva O, Palazzo J, Bilalovic N, Lee LM, Gatalica Z (2010) Adenoid cystic carcinomas of the breast have low Topo IIalpha expression but frequently overexpress EGFR protein without EGFR gene amplification. Hum Pathol 41:1617–1623. doi:10.1016/j.humpath.2010.04.013
Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LF, de Jong D, Van de Vijver MJ, Van’t Veer LJ, Peterse JL (2008) Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol 216:141–150. doi:10.1002/path.2407
Wetterskog D, Lopez-Garcia MA, Lambros MB, A’Hern R, Geyer FC, Milanezi F, Cabral MC, Natrajan R, Gauthier A, Shiu KK, Orr N, Shousha S, Gatalica Z, Mackay A, Palacios J, Reis-Filho JS, Weigelt B (2012) Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers. J Pathol 226:84–96. doi:10.1002/path.2974
Zhao X, Chao YL, Wan QB, Chen XM, Su P, Sun J, Tang Y (2011) Flavokawain B induces apoptosis of human oral adenoid cystic cancer ACC-2 cells via up-regulation of Bim and down-regulation of Bcl-2 expression. Can J Physiol Pharmacol 89:875–883. doi:10.1139/y11-088
Zukerberg LR, Yang WI, Gadd M, Thor AD, Koerner FC, Schmidt EV, Arnold A (1995) Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod Pathol Off J US Can Acad Pathol Inc 8:560–567
Acknowledgments
The authors thank Anna Szilágyi, Norbert Lippai, and Márta Jäckel for sending bACC cases for consultation purposes, Erzsebet Azumah for performing immunohistochemical assays, Krisztina Schlachter and Miklós Gergely Oláh for Adobe Photoshop management, Benedek Gyöngyösi for the qRT-PCR evaluation, and Barnabás Tóth for the statistical analysis.
Support grants: TÁMOP-4.2.2/B-10/1-2010-0013; TÁMOP-4.2.1/B-09/1/KMR-2010-0001; TÁMOP 4.2.4.A/2-11-1-2012-0001. Ethical approval: TUKEB 101/2012
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Supplementary 1
Calculated ΔCT values of 18 microRNAs in the investigated study groups (sACCs: salivary-gland-derived adenoid cystic carcinomas; sNs: normal salivary gland tissues; bACCs: breast-derived adenoid cystic carcinomas; bNs: normal breast tissues) (XLS 44 kb)
Supplementary 2
Results of Tukey test performed on ΔCT values of microRNA expression of the investigated study groups (sACCs: salivary-gland-derived adenoid cystic carcinomas; sNs: normal salivary gland tissues; bACCs: breast-derived adenoid cystic carcinomas; bNs: normal breast tissues) (XLSX 30 kb)
Supplementary 3
Hirsch-score values of cyclin D1 and Bcl-2 immunohistochemical analysis (bN: normal breast tissue; bACC: breast-derived adenoid cystic carcinoma; sN: normal salivary gland tissue; sACC: salivary-gland-derived adenoid cystic carcinoma) (DOCX 12 kb)
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Kiss, O., Tőkés, AM., Vranic, S. et al. Expression of miRNAs in adenoid cystic carcinomas of the breast and salivary glands. Virchows Arch 467, 551–562 (2015). https://doi.org/10.1007/s00428-015-1827-3
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DOI: https://doi.org/10.1007/s00428-015-1827-3