Translation of triple-negative breast cancer behavior from the xenograft model to human model
Abstract
Background: For xenograft models of triple-negative breast cancer (TNBC) to be valuable in development of molecularly-targeted drugs, careful characterization is essential to their validation. The present study aimed to validate the TNBC xenograft model with a specific focus on angiogenesis. Methods: Twelve TNBC xenograft tumors and 12 human breast cancer tumors (HTNBC) were included in this study. Both groups were grade III and p53 positive. Nuclear pleomorphism and mitotic count were analyzed by hematoxylin and eosin (H&E) stains respectively. Basal cytokeratin (CK5/6), vimentin, cathepsin-D, Ki-67 (for proliferation), and MVD-CD34 (for angiogenesis) markers were examined by immunohistochemistry (IHC). The association of Microvesseles density (MVD) with Ki-67, nuclear pleomorphism, and mitotic count was assessed in each group separately, and HTNBCs were compared with the xenograft group. Results: The xenograft models showed a significant correlation between angiogenesis (MVD) and cell proliferation (Ki-67), nuclear pleomorphism, and mitotic count (p= 0.0398; p= 0.020; p=0.001, respectively). The HTNBC group also showed a similar trend, except nuclear pleomorphism (p=0.193), which did not correlate with angiogenesis. Comparison between the two groups showed significant changes in cell proliferation (Ki-67 and vimentin). The difference in proliferation rate and vimentin expression between the two groups can be due to biological diversity between human and mice and epithelial-mesenchymal transition (EMT), respectively. Conclusion: Our results, re-emphasize the significance of angiogenic treatment therapy in patients with TNBC, and further validate the TNBC xenograft model as a valid model for drug discovery and development.Eroles P, Bosch A, Pérez-Fidalgo JA, Lluch A: Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev 38(6): 698-707, 2012.
Griffiths CL and Olin JL: Triple negative breast cancer: a brief review of its characteristics and treatment options. J Pharm Pract 25(3): 319-23, 2012.
Ismail-Khan R and Bui MM: A review of triple-negative breast cancer. Cancer Control 17(3): 173-6, 2010.
Rubovszky G, Udvarhelyi N, Horváth Z, Láng I, Kásler M: [Triple-negative breast carcinoma-rewiev of current literature]. Magy Onko 54(4): 325-35, 2010.
Narod SA: Breast cancer in young women. Nat Rev Clin Oncol 26:9(8): 460-70, 2012.
von Minckwitz G and Martin M: Neoadjuvant treatments for triple-negative breast cancer (TNBC). Ann Oncol 23 Suppl 6: 35-9, 2010.
Kerbel RS: Strategies for improving the clinical benefit of antiangiogenic drug based therapies for breast cancer, J Mammary Gland Biol Neoplasia 17(3-4): 229-39, 2012.
Shastry M and Yardley DA: Updates in the treatment of basal/triple-negative breast cancer. Curr Opin Obstet Gynecol 25(1): 40-8, 2013.
Mollard S, Mousseau Y, Baaj Y, Richard L, Cook-Moreau J, Monteil J, Funalot B, Sturtz FG: How can grafted breast cancer models be optimized? Cancer Biol Ther 15:12(10): 855-64, 2011.
Holliday DL and Speirs V: Choosing the right cell line for breast cancer research. Cancer Res Breast 12, 13(4): 215, 2011.
American Type Culture Collection (ATCC): http://www.atcc.org/products/all/HTB-26.aspx, 2014.
Lacroix M and Leclercq G: Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat 83(3): 249-89, 2004.
Wang K, Xie SM, He JJ, Ren Y, Xia HB, Zhang XW: [Establishment of a bioluminescent MDA-MB-231 cell line for in vivo imaging of human triple-negative breast cancer xenograft]. Nan Fang Yi Ke Da Xue Xue Bao 31(11): 1812-8, 2011.
Lips EH, Mulder L, Oonk A, van der Kolk LE, Hogervorst FB, Imholz AL, Wesseling J, Rodenhuis S, Nederlof PM: Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer 28:108(10): 2172-7, 2013.
Turkoz FP, Solak M, Petekkaya I, Keskin O, Kertmen N, Sarici F, Arik Z, Babacan T, Ozisik Y, Altundag K: The prognostic impact of obesity on molecular subtypes of breast cancer in premenopausal women. J BUON 18(2): 335-41, 2013.
Choi YL, Oh E, Park S, Kim Y, Park YH, Song K, Cho EY, Hong YC, Choi JS, Lee JE, Kim JH, Nam SJ, Im YH, Yang JH, Shin YK: Triple-negative, basal-like, and quintuple-negative breast cancers: better prediction model for survival. BMC Cancer 23:10: 507, 2010.
Uzzan B, Nicolas P, Cucherat M, Perret GY: Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res 1:64(9): 2941-55, 2004.
Muhammadnejad A, Keyhani E, Mortazavi P, Behjati F, Haghdoost I: Overexpression of her-2/neu in malignant mammary tumors; translation of clinicopathological features from dog to human. Asian Pac J Cancer Prev 13(12): 6415-21, 2012.
Mrklić I, Ćapkun V, Pogorelić Z, Tomić S: Prognostic value of Ki-67 proliferating index in triple negative breast carcinomas. Pathol Res Pract 209(5): 296-301, 2013.
Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, Lee SH, Han W, Kim DW, Kim TY, Park IA, Noh DY, Heo DS, Bang YJ: Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res 2:13(2): R2, 2011.
Muhammadnejad S, Muhammadnejad A, Haddadi M, Oghabian MA, Mohagheghi MA, Tirgari F, Sadeghi-Fazel F, Amanpour S: Correlation of microvessel density with nuclear pleomorphism, mitotic count and vascular invasion in breast and prostate cancers at preclinical and clinical levels. Asian Pac J Cancer Prev 14(1): 63-8, 2013.
Rakha EA, van Deurzen CH, Paish EC, Macmillan RD, Ellis IO, Lee AH: Pleomorphic lobular carcinoma of the breast: is it a prognostically significant pathological subtype independent of histological grade? Mod Pathol 26(4): 496-501, 2013.
Bussolati G, Marchiò C, Gaetano L, Lupo R, Sapino A: Pleomorphism of the nuclear envelope in breast cancer: a new approach to an old problem. J Cell Mol Med 12(1): 209-18, 2008.
Galante E, Guzzon A, Gallus G, Mauri M, Bono A, De Carli A, Merson M, Di Pietro S: Prognostic significance of the growth rate of breast cancer: preliminary evaluation on the follow-up of 196 breast cancers. Tumori 67(4): 333-40, 1981.
Vieira IT, de Senna V, Harper PR, Shahani AK: Tumour doubling times and the length bias in breast cancer screening programmers. Health Care Manag Sci 14(2): 203-11, 2011.
Liu ZB, Wu J, Ping B, Feng LQ, Shen ZZ, Shao ZM: [Expression of CK5/6 and CK17 and its correlation with prognosis of triple-negative breast cancer patients]. Zhonghua Zhong Liu Za Zhi 30(8): 610-4, 2008.
Choi Y, Lee HJ, Jang MH, Gwak JM, Lee KS, Kim EJ, Kim HJ, Lee HE, Park SY: Epithelial-mesenchymal transition increases during the progression of in situ to invasive basal-like breast cancer. Hum Pathol 44(11): 2581-9, 2013.
Choi Y, Lee HJ, Jang MH, Gwak JM, Lee KS, Kim EJ, Kim HJ, Lee HE, Park SY: Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Oncogene 44(11): 2581-9, 2013.
Yamashita N, Tokunaga E, Kitao H, Hisamatsu Y, Taketani K, Akiyoshi S, Okada S, Aishima S, Morita M, Maehara Y: Vimentin as a poor prognostic factor for triple-negative breast cancer. J Cancer Res Clin Oncol 139(5): 739-46, 2013.
Maynadier M, Farnoud R, Lamy PJ, Laurent-Matha V, Garcia M, Rochefort H: Cathepsin D stimulates the activities of secreted plasminogen activators in the breast cancer acidic environment. Int J Oncol 43(5): 1683-90, 2013.
Rochefort H, Garcia M, Glondu M, Laurent V, Liaudet E, Rey JM, Roger P: Cathepsin D in breast cancer: mechanisms and clinical applications, a 1999 overview. Clin Chim Acta 15:291(2): 157-70, 2000.
| Files | ||
| Issue | Vol 8 No 3 (2016) | |
| Section | Original Articles | |
| Keywords | ||
| Triple-negative breast cancer Xenograft models Angiogenesis Translational research Validity | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
