Prognostic significance of CD117 expression and TP53 missense mutations in triple-negative breast cancer

Luo,Yanli; Huang,Wentao; Zhang,Huizhen; Liu,Guang

doi:10.3892/ol.2018.8104

Prognostic significance of CD117 expression and TP53 missense mutations in triple-negative breast cancer

Authors:
- Yanli Luo
- Wentao Huang
- Huizhen Zhang
- Guang Liu
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Affiliations: Department of Pathology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China, Department of Vascular Surgery, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, P.R. China
Published online on: February 22, 2018 https://doi.org/10.3892/ol.2018.8104
Pages: 6161-6170
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triple-negative breast cancer (TNBC) is extremely aggressive and associated with poor prognosis. There are no known predictive or prognostic markers for TNBC. Inhibition of tumor protein P53 (TP53) has been demonstrated to increase the levels of cluster of differentiation 117 (CD117) in human colorectal cancer cells. However, the function of TP53 in the regulation of CD117 in TNBC has, to the best of our knowledge, not been reported. In the present study, the association between the expression of CD117 protein and TP53 mutations was investigated, and their prognostic value in patients with TNBC was assessed. A total of 58 TNBC and 48 non‑TNBC breast cancer tissue samples were assessed for the expression of CD117, p53 and TP53 mutations. The marker of proliferation Ki‑67 (MKI67) proliferation index and vascular invasion index (obtained by measuring D2‑40 and CD34) was investigated via immunohistochemistry, and mutations in exons 4-8 of TP53 were measured using direct sequencing. Associations between CD117 and p53 levels or TP53 mutations and clinical parameters were statistically evaluated. The rates of CD117 or MKI67 positivity, CD117+/TP53 missense mutation+, TP53 missense mutations or recurrence were significantly higher in patients with TNBC than in patients with non-TNBC. In TNBC tissues, the presence of CD117 was associated with TP53 missense mutations (P=0.031), vascular invasion, recurrence and MKI67. CD117+/TP53 missense mutation+ also associated with vascular invasion, recurrence and MKI67. Under univariate analysis, MKI67, vascular invasion, CD117, CD117+/TP53 missense mutation+ and TP53 missense mutations were associated with the overall survival of patients with TNBC. Multivariate analysis revealed that vascular invasion and CD117+/TP53 missense mutation+ in primary tumors were independent prognostic factors in patients with TNBC. In conclusion, CD117+/TP53 missense mutation+ was associated with MKI67, vascular invasion and tumor recurrence in TNBC. The presence of CD117 and TP53 missense mutations together in the primary tumors was an independent prognostic factor for survival of patients with TNBC.

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1	Foulkes WD, Smith IE and Reis-Filho JS: Triple-negative breast cancer. N Engl J Med. 363:1938–1948. 2010. View Article : Google Scholar : PubMed/NCBI
2	Changavi AA, Shashikala A and Ramji AS: Epidermal growth factor receptor expression in triple negative and nontriple negative breast carcinomas. J Lab Physicians. 7:79–83. 2015. View Article : Google Scholar : PubMed/NCBI
3	Metzger-Filho O, Tutt A, de Azambuja E, Saini KS, Viale G, Loi S, Bradbury I, Bliss JM, Azim HA Jr, Ellis P, et al: Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol. 30:1879–1887. 2012. View Article : Google Scholar : PubMed/NCBI
4	Lasota J and Miettinen M: Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 53:245–266. 2008. View Article : Google Scholar : PubMed/NCBI
5	Yoshida C, Tsuji AB, Sudo H, Sugyo A, Kikuchi T, Koizumi M, Arano Y and Saga T: Therapeutic efficacy of c-kit-targeted radioimmunotherapy using 90Y-labeled anti-c-kit antibodies in a mouse model of small cell lung cancer. PLoS One. 8:e592482013. View Article : Google Scholar : PubMed/NCBI
6	Thike AA, Iqbal J, Cheok PY, Chong AP, Tse GM, Tan B, Tan P, Wong NS and Tan PH: Triple negative breast cancer: Outcome correlation with immunohistochemical detection of basal markers. Am J Surg Pathol. 34:956–964. 2010. View Article : Google Scholar : PubMed/NCBI
7	Blassl C, Kuhlmann JD, Webers A, Wimberger P, Fehm T and Neubauer H: Gene expression profiling of single circulating tumor cells in ovarian cancer-Establishment of a multi-marker gene panel. Mol Oncol. 10:1030–1042. 2016. View Article : Google Scholar : PubMed/NCBI
8	Fan H, Yuan Y, Wang J, Zhou F, Zhang M, Giercksky KE, Nesland JM and Suo Z: CD117 expression in operable oesophageal squamous cell carcinomas predicts worse clinical outcome. Histopathology. 62:1028–1037. 2013. View Article : Google Scholar : PubMed/NCBI
9	Kashiwagi S, Yashiro M, Takashima T, Aomatsu N, Kawajiri H, Ogawa Y, Onoda N, Ishikawa T, Wakasa K and Hirakawa K: c-Kit expression as a prognostic molecular marker in patients with basal-like breast cancer. Br J Surg. 100:490–496. 2013. View Article : Google Scholar : PubMed/NCBI
10	Medinger M, Kleinschmidt M, Mross K, Wehmeyer B, Unger C, Schaefer HE, Weber R and Azemar M: c-kit (CD117) expression in human tumors and its prognostic value: An immunohistochemical analysis. Pathol Oncol Res. 16:295–301. 2010. View Article : Google Scholar : PubMed/NCBI
11	Jansson S, Bendah PO, Grabau DA, Falck AK, Fernö M, Aaltonen K and Rydén L: The three receptor tyrosine kinases c-KIT, VEGFR2 and PDGFRα, closely spaced at 4q12, show increased protein expression in triple-negative breast cancer. PLoS One. 9:e1021762014. View Article : Google Scholar : PubMed/NCBI
12	Kim HW, Lee HM, Hwang SH, Ahn SG, Lee KA and Jeong J: Patterns and biologic features of p53 mutation types in Korean breast cancer patients. J Breast Cancer. 17:1–7. 2014. View Article : Google Scholar : PubMed/NCBI
13	Kruiswijk F, Labuschagne CF and Vousden KH: p53 in survival, death and metabolic health: A lifeguard with a licence to kill. Nat Rev Mol Cell Biol. 16:393–405. 2015. View Article : Google Scholar : PubMed/NCBI
14	Fernández-Cuesta L, Oakman C, Falagan-Lotsch P, Smoth KS, Quinaux E, Buyse M, Dolci MS, Azambuja ED, Hainaut P, Dell'orto P, et al: Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: Results from the BIG 02–98 phase III trial. Breast Cancer Res. 14:R702012. View Article : Google Scholar : PubMed/NCBI
15	Chae BJ, Bae JS, Lee A, Park WC, Seo YJ, Song BJ, Kim JS and Jung SS: p53 as a specific prognostic factor in triple-negative breast cancer. Jpn J Clin Oncol. 39:217–224. 2009. View Article : Google Scholar : PubMed/NCBI
16	Olivier M, Langerød A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bièche I, et al: The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res. 12:1157–1167. 2006. View Article : Google Scholar : PubMed/NCBI
17	Foedermayr M, Sebesta M, Rudas M, Berghoff AS, Promberger R, Preusser M, Dubsky P, Fitzal F, Gnant M, Steger GG, et al: BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy. Cancer Chemother Pharmacol. 73:771–778. 2014. View Article : Google Scholar : PubMed/NCBI
18	Siemens H, Jackstadt R, Kaller M and Hermeking H: Repression of c-Kit by p53 is mediated by miR-34 and is associated with reduced chemoresistance, migration and stemness. Oncotarget. 4:1399–1415. 2013. View Article : Google Scholar : PubMed/NCBI
19	Mittendorf EA, Ballman KV, McCall LM, Yi M, Sahin AA, Bedrosian I, Hansen N, Gabram S, Hurd T, Giuliano AE and Hunt KK: Evaluation of the stage IB designation of the American Joint Committee on Cancer staging system in breast cancer. J Clin Oncol. 33:1119–1127. 2015. View Article : Google Scholar : PubMed/NCBI
20	Penault-Llorca F, André F, Sagan C, Lacroix-Triki M, Denoux Y, Verriele V, Jacquemier J, Baranzelli MC, Bibeau F, Antoine M, et al: Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 27:2809–2815. 2009. View Article : Google Scholar : PubMed/NCBI
21	Huang Q, Li F, Liu X, Li W, Shi W, Liu FF, O'Sullivan B, He Z, Peng Y, Tan AC, et al: Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med. 17:860–866. 2011. View Article : Google Scholar : PubMed/NCBI
22	Yaman S, Gumuskaya B, Ozkan C, Aksoy S, Guler G and Altundag K: Lymphatic and capillary invasion patterns in triple negative breast cancer. Am Surg. 78:1238–1242. 2012.PubMed/NCBI
23	Varga Z, Noske A, Ramach C, Padberg B and Moch H: Assessment of HER2 status in breast cancer: Overall positivity rate and accuracy by fluorescence in situ hybridization and immunohistochemistry in a single institution over 12 years: A quality control study. BMC Cancer. 13:6152013. View Article : Google Scholar : PubMed/NCBI
24	Yue YI, Astvatsaturyan K, Cui X, Zhang X, Fraass B and Bose S: Stratification of prognosis of triple-negative breast cancer patients using combinatorial biomarkers. PLoS One. 11:e01496612016. View Article : Google Scholar : PubMed/NCBI
25	Ricciardi GR, Adamo B, Ieni A, Licata L, Cardia R, Ferraro G, Franchina T, Tuccari G and Adamo V: Androgen Receptor (AR), E-cadherin, and Ki-67 as emerging targets and novel prognostic markers in Triple-Negative Breast Cancer (TNBC) patients. PLoS One. 10:e01283682015. View Article : Google Scholar : PubMed/NCBI
26	Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, Lee SH, Han W, Kim DW, Kim TY, et al: Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res. 13:R222011. View Article : Google Scholar : PubMed/NCBI
27	Sabatier R, Jacquemier J, Bertucci F, Esterni B, Finetti P, Azario F, Birnbaum D, Viens P, Gonçalves A and Extra JM: Peritumoural vascular invasion: A major determinant of triple-negative breast cancer outcome. Eur J Cancer. 47:1537–1545. 2011. View Article : Google Scholar : PubMed/NCBI
28	Simon R, Panussis S, Maurer R, Spichtin H, Glatz K, Tapia C, Mirlacher M, Rufle A, Torhorst J and Sauter G: KIT (CD117)-positive breast cancers are infrequent and lack KIT gene mutations. Clin Cancer Res. 10:178–183. 2004. View Article : Google Scholar : PubMed/NCBI
29	Kanapathy Pillai SK, Tay A, Nair S and Leong CO: Triple-negative breast cancer is associated with EGFR, CK5/6 and c-KIT expression in Malaysian women. BMC Clin Pathol. 12:182012. View Article : Google Scholar : PubMed/NCBI
30	Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, et al: Immuno-histochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 10:5367–5374. 2004. View Article : Google Scholar : PubMed/NCBI
31	Fountzilas G, Giannoulatou E, Alexopoulou Z, Zagouri F, Timotheadou E, Papadopoulou K, Lakis S, Bobos M, Poulios C, Sotiropoulou M, et al: TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting. Oncotarget. 7:32731–32753. 2016. View Article : Google Scholar : PubMed/NCBI
32	Kim Y, Kim J, Lee HD, Jeong J, Lee W and Lee KA: Spectrum of EGFR gene copy number changes and KRAS gene mutation status in korean triple negative breast cancer patients. PLoS One. 8:e790142013. View Article : Google Scholar : PubMed/NCBI
33	Végran F, Rebucci M, Chevrier S, Cadouot M, Boidot R and Lizard-Nacol S: Only missense mutations affecting the DNA binding domain of p53 influence outcomes in patients with breast carcinoma. PLoS One. 8:e551032013. View Article : Google Scholar : PubMed/NCBI
34	Kim JY, Park K, Jung HH, Lee E, Cho EY, Lee KH, Bae SY, Lee SK, Kim SW, Lee JE, et al: Association between mutation and expression of TP53 as a potential prognostic marker of triple-negative breast cancer. Cancer Res Treat. 48:1338–1350. 2016. View Article : Google Scholar : PubMed/NCBI
35	Taylor NJ, Nikolaishvili-Feinberg N, Midkiff BR, Conway K, Millikan RC and Geradts J: Rational manual and automated scoring thresholds for the immunohistochemical detection of TP53 missense mutations in human breast carcinomas. Appl Immunohistochem Mol Morphol. 24:398–404. 2016. View Article : Google Scholar : PubMed/NCBI
36	Pandrangi SL, Raju Bagadi SA, Sinha NK, Kumar M, Dada R, Lakhanpal M, Soni A, Malvia S, Simon S, Chintamani C, et al: Establishment and characterization of two primary breast cancer cell lines from young Indian breast cancer patients: Mutation analysis. Cancer Cell Int. 14:142014. View Article : Google Scholar : PubMed/NCBI
37	Dobes P, Podhorec J, Coufal O, Jureckova A, Petrakova K, Vojtesek B and Hrstka R: Influence of mutation type on prognostic and predictive values of TP53 status in primary breast cancer patients. Oncol Rep. 32:1695–1702. 2014. View Article : Google Scholar : PubMed/NCBI
38	Silwal-Pandit L, Vollan HK, Chin SF, Rueda OM, McKinney S, Osako T, Quigley DA, Kristensen VN, Aparicio S, Børresen-Dale AL, et al: TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res. 20:3569–3580. 2014. View Article : Google Scholar : PubMed/NCBI
39	Abraham SA, Hopcroft LE, Carrick E, Drotar ME, Dunn K, Williamson AJ, Korfi K, Baquero P, Park LE, Scott MT, et al: Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature. 534:341–346. 2016. View Article : Google Scholar : PubMed/NCBI
40	Yogev O, Barker K, Sikka A, Almeida GS, Hallsworth A, Smith LM, Jamin Y, Ruddle R, Koers A, Webber HT, et al: p53 loss in MYC-driven neuroblastoma leads to metabolic adaptations supporting radioresistance. Cancer Res. 76:3025–3035. 2016. View Article : Google Scholar : PubMed/NCBI
41	Lai JH, Fleming KE, Ly TY, Pasternak S, Godlewski M, Doucette S and Walsh NM: Pure versus combined Merkel cell carcinomas: Immunohistochemical evaluation of cellular proteins (p53, Bcl-2 and c-kit) reveals significant overexpression of p53 in combined tumors. Hum Pathol. 46:1290–1296. 2015. View Article : Google Scholar : PubMed/NCBI