Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer

Jeong,Young  Ju; Park,Sung  Hwan; Mun,Sung  Hee; Kwak,Sang  Gyu; Lee,Sun‑Jae; Oh,Hoon  Kyu

doi:10.3892/ol.2017.7617

Association between lysyl oxidase and fibrotic focus in relation with inflammation in breast cancer

Authors:
- Young Ju Jeong
- Sung Hwan Park
- Sung Hee Mun
- Sang Gyu Kwak
- Sun‑Jae Lee
- Hoon Kyu Oh
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Affiliations: Department of Surgery, College of Medicine, Catholic University of Daegu, Daegu 705-718, Repulic of South Korea, Department of Radiology, College of Medicine, Catholic University of Daegu, Daegu 705-718, Repulic of South Korea, Department of Medical Statistics, College of Medicine, Catholic University of Daegu, Daegu 705-718, Repulic of South Korea, Department of Pathology, College of Medicine, Catholic University of Daegu, Daegu 705-718, Repulic of South Korea
Published online on: December 14, 2017 https://doi.org/10.3892/ol.2017.7617
Pages: 2431-2440

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Abstract

We hypothesized that lysyl oxidase (LOX) contributes to the formation of fibrotic focus (FF) in association with inflammation and serves a significant role in breast carcinogenesis. In the present study, the association between the expression of LOX family members and FF with regards to with inflammation was analyzed, and the prognostic significance of LOX and FF in breast cancer was investigated. Immunohistochemical staining for LOX, LOX‑like protein (LOXL) 1, LOXL2 and LOXL3 was performed in primary breast cancer tissues. The status of FF within the tumor was assessed, including size and grade. Levels of inflammatory markers, intratumoral and peritumoral lymphocyte infiltration were also evaluated. The clinicopathological characteristics were evaluated from the medical records of patients. In the present study, the expression of LOX family members was not associated with the presence of FF. FF was identified to be associated with intratumoral and peritumoral inflammation, tumor stage, larger tumor size, lymph node metastasis, high histologic grade, and p53 expression. LOX and LOXL3 were associated with intratumoral, and peritumoral inflammation. Furthermore, LOXL1 was associated with intratumoral inflammation and interleukin‑4. In addition, LOX was associated with cluster of differentiation 8+ T cells. LOXL3 was associated with expression of ER and PR, and molecular subtype. In the survival analysis, overall survival time was statistically significantly longer in the FF‑negative compared with that in the FF‑positive group. In conclusion, it was demonstrated that FF and the expression of LOX family members were associated with inflammation in breast cancer. FF was associated with poor prognostic markers of breast cancer. Further studies are required to clarify the mechanisms underlying the association between the LOX family, FF and inflammation in breast cancer.

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1	Pupa SM, Ménard S, Forti S and Tagliabue E: New insights into the role of extracellular matrix during tumor onset and progression. J Cell Physiol. 192:259–267. 2002. View Article : Google Scholar : PubMed/NCBI
2	Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SFT, Csiszar K, Giaccia A, Weninger W, et al: Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 139:891–906. 2009. View Article : Google Scholar : PubMed/NCBI
3	Gilkes DM, Semenza GL and Wirtz D: Hypoxia and the extracellular matrix: Drivers of tumour metastasis. Nat Rev Cancer. 14:430–439. 2014. View Article : Google Scholar : PubMed/NCBI
4	Acerbi I, Cassereau L, Dean I, Shi Q, Au A, Park C, Chen YY, Liphardt J, Hwang ES and Weaver VM: Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb). 7:1120–1134. 2015. View Article : Google Scholar : PubMed/NCBI
5	Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G and Erler JT: LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73:1721–1732. 2013. View Article : Google Scholar : PubMed/NCBI
6	Csiszar K: Lysyl oxidase: A novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol. 70:1–32. 2001. View Article : Google Scholar : PubMed/NCBI
7	Payne SL, Hendrix MJC and Kirschmann DA: Paradoxical roles for lysyl oxidases in cancer-a prospect. J Cell Biochem. 101:1338–1354. 2007. View Article : Google Scholar : PubMed/NCBI
8	Smith-Mungo LI and Kagan HM: Lysyl oxidase: Properties, regulation and multiple functions in biology. Matrix Biol. 16:387–398. 1998. View Article : Google Scholar : PubMed/NCBI
9	Kagan HM and Li W: Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem. 88:660–672. 2003. View Article : Google Scholar : PubMed/NCBI
10	Molnar J, Fong KSK, He QP, Hayashi K, Kim Y, Fong SF, Fogelgren B, Szauter KM, Mink M and Csiszar K: Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochim Biophys Acta. 1647:220–224. 2003. View Article : Google Scholar : PubMed/NCBI
11	Lucero HA and Kagan HM: Lysyl oxidase: An oxidative enzyme and effector of cell function. Cell Mol Life Sci. 63:2304–2316. 2006. View Article : Google Scholar : PubMed/NCBI
12	Baker AM, Cox TR, Bird D, Lang G, Murray GI, Sun XF, Southall SM, Wilson JR and Erler JT: The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. J Natl Cancer Inst. 103:407–424. 2011. View Article : Google Scholar : PubMed/NCBI
13	Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, Chi JT, Jeffrey SS and Giaccia AJ: Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 440:1222–1226. 2006. View Article : Google Scholar : PubMed/NCBI
14	Barker HE, Chang J, Cox TR, Lang G, Bird D, Nicolau M, Evans HR, Gartland A and Erler JT: LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res. 71:1561–1572. 2011. View Article : Google Scholar : PubMed/NCBI
15	Cox TR and Erler JT: Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Dis Model Mech. 4:165–178. 2011. View Article : Google Scholar : PubMed/NCBI
16	Hasebe T, Tsuda H, Hirohashi S, Shimosato Y, Iwai M, Imoto S and Mukai K: Fibrotic focus in invasive ductal carcinoma: An indicator of high tumor aggressiveness. Jpn J Cancer Res. 87:385–394. 1996. View Article : Google Scholar : PubMed/NCBI
17	Van den Eynden GG, Colpaert CG, Couvelard A, Pezzella F, Dirix LY, Vermeulen PB, Van Marck EA and Hasbe T: A fibrotic focus is a prognostic factor and a surrogate marker for hypoxia and (lymph)angiogenesis in breast cancer: Review of the literature and proposal on the criteria of evaluation. Histopathology. 51:440–451. 2007. View Article : Google Scholar : PubMed/NCBI
18	Ueha S, Shand FH and Matsushima K: Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis. Front Immunol. 3:712012. View Article : Google Scholar : PubMed/NCBI
19	López-Novoa JM and Nieto MA: Inflammation and EMT: An alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 1:303–314. 2009. View Article : Google Scholar : PubMed/NCBI
20	Jeong YJ, Bong JG, Park SH, Choi JI and Oh HK: Expression of leptin, leptin receptor, adiponectin, and adiponectin receptor in ductal carcinoma in situ and invasive breast cancer. J Breast Cancer. 14:96–103. 2011. View Article : Google Scholar : PubMed/NCBI
21	Radisky DC, Kenny PA and Bissell MJ: Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 101:830–839. 2007. View Article : Google Scholar : PubMed/NCBI
22	Ertz N: Cancer: Opening LOX to metastasis. Nature. 522:41–42. 2015. View Article : Google Scholar : PubMed/NCBI
23	Nishioka T, Eustace A and West C: Lysyl oxidase: From basic science to future cancer treatment. Cell Struct Funct. 37:75–80. 2012. View Article : Google Scholar : PubMed/NCBI
24	Leight JL, Wozniak MA, Chen S, Lynch ML and Chen CS: Matrix rigidity regulates a switch between TGF-β 1-induced apoptosis and epithelial-mesenchymal transition. Mol Biol Cell. 23:781–791. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wynn TA and Barron L: Macrophages: Master regulators of inflammation and fibrosis. Semin Liver Dis. 30:245–257. 2010. View Article : Google Scholar : PubMed/NCBI
26	Luzina IG, Todd NW, Iacono AT and Atamas SP: Roles of T lymphocytes in pulmonary fibrosis. J Leuko Biol. 83:237–244. 2008. View Article : Google Scholar : PubMed/NCBI
27	Meldrum KK, Metcalfe P, Leslie JA, Misseri R, Hile KL and Meldrum DR: TNF-alpha neutralization decreases nuclear factor-kappaB activation and apoptosis during renal obstruction. J Surg Res. 131:181–188. 2006. View Article : Google Scholar
28	Tashiro K, Tamada S, Kuwabara N, Komiya T, Takekida K, Asai T, Iwao H, Sugimura K, Matsumura Y, Takaoka M, et al: Attenuation of renal fibrosis by proteasome inhibition in rat obstructive nephropathy: Possible role of nuclear factor kappaB. Int J Mol Med. 12:587–592. 2003.PubMed/NCBI
29	Karin M and Greten FR: NF-kappaB. Linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005. View Article : Google Scholar : PubMed/NCBI
30	Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, Dargemont C, de Herreros AG, Bellacosa A and Larue L: Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. 26:7445–7456. 2007. View Article : Google Scholar : PubMed/NCBI
31	Kim HJ, Litzenburger BC, Cui X, Delgado DA, Grabiner BC, Lin X, Lewis MT, Gottardis MM, Wong TW, Attar RM, et al: Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail. Mol Cell Biol. 27:3165–3175. 2007. View Article : Google Scholar : PubMed/NCBI
32	Denko NC, Fontana LA, Hudson KM, Sutphin PD, Raychaudhuri S, Altman R and Giaccia AJ: Investigating hypoxic tumor physiology through gene expression patterns. Oncogene. 22:5907–5914. 2003. View Article : Google Scholar : PubMed/NCBI
33	Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, et al: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 117:3810–3820. 2007.PubMed/NCBI
34	Nagai S and Toi M: Interleukin-4 and breast cancer. Breast Cancer. 7:181–186. 2000. View Article : Google Scholar : PubMed/NCBI
35	Hasebe T, Sasaki S, Imoto S, Muki K, Yokose T and Ochiai A: Prognostic significance of fibrotic focus in invasive ductal carcinoma of the breast: A prospective observational study. Mod Pathol. 15:502–516. 2002. View Article : Google Scholar : PubMed/NCBI
36	Hollosi P, Yakushiji JK, Fong KS, Csiszar K and Fong SF: Lysyl oxidase-like 2 promotes migration in noninvasive breast cancer cells no in normal breast epithelial cells. Int J Cancer. 125:318–327. 2009. View Article : Google Scholar : PubMed/NCBI
37	Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K and Hendrix MJ: A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 62:4478–4483. 2002.PubMed/NCBI
38	Hellman J, Jansen MP, Ruigrok-Ritstier K, van Staveren IL, Look MP, Meijer-van Gelder ME, Sieuwerts AM, Klijn JG, SleiJfer S, Foekens JA and Berns EM: Association of an extracellular matrix gene cluster with breast cancer prognosis and endocrine therapy response. Clin Cancer Res. 14:5555–5564. 2008. View Article : Google Scholar : PubMed/NCBI
39	Patani N, Jiang W, Newbold R and Mokbel K: Prognostic implications of carboxyl-terminus of Hsc70 interacting protein and lysyl-oxidase expression in human breast cancer. J Carcinog. 9:92010. View Article : Google Scholar : PubMed/NCBI
40	Peinado H, Moreno-Bueno G, Hardisson D, Pérez-Gómez E, Santos V, Mendiola M, de Diego JI, Nistal M, Quintanilla M, Portillo F and Cano A: Lysyl oxidase-like 2 as a new poor prognosis marker of squamous cell carcinomas. Cancer Res. 68:4541–4550. 2008. View Article : Google Scholar : PubMed/NCBI
41	McSherry EA, McGoldrick A, Kay EW, Hopkins AM, Gallagher WM and Dervan PA: Formalin-fixed paraffin-embedded clinical tissues show spurious copy number changes in array-CGH profiles. Clin Genet. 72:441–447. 2007. View Article : Google Scholar : PubMed/NCBI