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01-10-2019 | Metastasis | Research Paper

Co-expression of carcinoembryonic antigen-related cell adhesion molecule 6 and 8 inhibits proliferation and invasiveness of breast carcinoma cells

Authors: Erina Iwabuchi, Yasuhiro Miki, Yoshiaki Onodera, Yukiko Shibahara, Kiyoshi Takagi, Takashi Suzuki, Takanori Ishida, Hironobu Sasano

Published in: Clinical & Experimental Metastasis | Issue 5/2019

Abstract

The carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6 and CEACAM8 form heterodimers and exert their effects. Therefore, we examined the effects of CEACAM6 and CEACAM8 co-expression in breast cancer. We first studied CEACAM6/8 expression using immunohistochemistry in 109 patients with breast cancer. We then established MCF-7 cells that were stably transfected with CEACAM8 and studied cell proliferation, invasion and adhesion. The number of CEACAM6 and CEACAM8 double-positive breast carcinoma cells significantly increased in patients with low histopathological grade and stage. Proximity ligation assay (PLA) confirmed high CEACAM6/8 expression in MCF-7 cells. CEACAM6/8 expression promoted the adhesion of MCF-7 cells to endothelial cell monolayers but inhibited their invasion and proliferation. Furthermore, CEACAM6 status in carcinoma cells was significantly higher in bone than in lung metastases. CEACAM6/8 expression is associated with the inhibition of vascular invasion and cell proliferation. CEACAM6 expression was also considered to be involved in bone metastases of breast cancer. This is the first study to demonstrate the possible role of CEACAM6/8 heterodimer and CEACAM6 expression in breast cancer patients.

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Beauchemin N, Arabzadeh A (2013) Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev 32:643–671. https://doi.org/10.1007/s10555-013-9444-6 CrossRefPubMed

Blumenthal RD, Leon E, Hansen HJ, Goldenberg DM (2007) Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers. BMC Cancer 7:2. https://doi.org/10.1186/1471-2407-7-2 CrossRefPubMedPubMedCentral

Bamberger AM, Kappes H, Methner C et al (2002) Expression of the adhesion molecule CEACAM1 (CD66a, BGP, C-CAM) in breast cancer is associated with the expression of the tumor-suppressor genes Rb, Rb2, and p27. Virchows Arch 440:139–144. https://doi.org/10.1007/s00428-001-0554-0 CrossRefPubMed

Wakabayashi-Nakao K (2014) Carcinoembryonic antigen-related cell adhesion molecule 4 (CEACAM4) is specifically expressed in medullary thyroid carcinoma cells. Biomed Res 35:237–242. https://doi.org/10.2220/biomedres.35.237 CrossRefPubMed

Yoshida K, Ueno S, Iwao T et al (2003) Screening of genes specifically activated in the pancreatic juice ductal cells from the patients with pancreatic ductal carcinoma. Cancer Sci 94:263–270. https://doi.org/10.1111/j.1349-7006.2003.tb01431.x CrossRefPubMed

Lee JS, Park S, Park JM et al (2013) Elevated levels of serum tumor markers CA 15 – 3 and CEA are prognostic factors for diagnosis of metastatic breast cancers. Breast Cancer Res Treat 141:477–484. https://doi.org/10.1007/s10549-013-2695-7 CrossRefPubMed

Lewis-Wambi JS, Cunliffe HE, Kim HR et al (2008) Overexpression of CEACAM6 promotes migration and invasion of oestrogen-deprived breast cancer cells. Eur J Cancer 44:1770–1779. https://doi.org/10.1016/j.ejca.2008.05.016 CrossRefPubMedPubMedCentral

Balk-Møller E, Kim J, Hopkinson B et al (2014) A marker of endocrine receptor-positive cells, CEACAM6, is shared by two major classes of breast cancer: Luminal and HER2-enriched. Am J Pathol 184:1198–1208. https://doi.org/10.1016/j.ajpath.2013.12.013 CrossRefPubMed

Bonsor DA, Günther S, Beadenkopf R et al (2015) Diverse oligomeric states of CEACAM IgV domains. Proc Natl Acad Sci USA 112:201509511. https://doi.org/10.1073/pnas.1509511112 CrossRef

10.

Goddard DS, Yamanaka KI, Kupper TS, Jones DA (2005) Activation of neutrophils in cutaneous T-cell lymphoma. Clin Cancer Res 11:8243–8249. https://doi.org/10.1158/1078-0432.CCR-05-1434 CrossRefPubMed

11.

Zhao L, Xu S, Fjaertoft G et al (2004) An enzyme-linked immunosorbent assay for human carcinoembryonic antigen-related cell adhesion molecule 8, a biological marker of granulocyte activities in vivo. J Immunol Methods 293:207–214. https://doi.org/10.1016/j.jim.2004.08.009 CrossRefPubMed

12.

Jensen HK, Donskov F, Marcussen N et al (2009) Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 27:4709–4717. https://doi.org/10.1200/JCO.2008.18.9498 CrossRefPubMed

13.

Li Y-W, Qiu S-J, Fan J et al (2011) Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 54:497–505. https://doi.org/10.1016/j.jhep.2010.07.044 CrossRefPubMed

14.

Ilie M, Hofman V, Ortholan C et al (2012) Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer 118:1726–1737. https://doi.org/10.1002/cncr.26456 CrossRefPubMed

15.

Rao H-L, Chen J-W, Li M et al (2012) Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS ONE 7:e30806. https://doi.org/10.1371/journal.pone.0030806 CrossRefPubMedPubMedCentral

16.

Carus A, Ladekarl M, Hager H et al (2013) Tumour-associated CD66b+ neutrophil count is an independent prognostic factor for recurrence in localised cervical cancer. Br J Cancer 108:2116–2122. https://doi.org/10.1038/bjc.2013.167 CrossRefPubMedPubMedCentral

17.

Lasa A, Serrano E, Carricondo M et al (2008) High expression of CEACAM6 and CEACAM8 mRNA in acute lymphoblastic leukemias. Ann Hematol 87:205–211. https://doi.org/10.1007/s00277-007-0388-1 CrossRefPubMed

18.

Hasselbalch HC, Skov V, Larsen TS et al (2011) High expression of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 6 and 8 in primary myelofibrosis. Leuk Res 35:1330–1334. https://doi.org/10.1016/j.leukres.2011.03.013 CrossRefPubMed

19.

Skubitz KM, Skubitz APN (2008) Interdependency of CEACAM-1, -3, -6, and – 8 induced human neutrophil adhesion to endothelial cells. J Transl Med 6:78. https://doi.org/10.1186/1479-5876-6-78 CrossRefPubMedPubMedCentral

20.

Iwabuchi E, Miki Y, Ono K et al (2017) In situ detection of estrogen receptor dimers in breast carcinoma cells in archival materials using proximity ligation assay (PLA). J Steroid Biochem Mol Biol 165:159–169. https://doi.org/10.1016/j.jsbmb.2016.05.022 CrossRefPubMed

21.

Iwabuchi E, Miki Y, Ono K et al (2017) In situ evaluation of estrogen receptor dimers in breast carcinoma cells: visualization of protein-protein interactions. Acta Histochem Cytochem 50:85–93. https://doi.org/10.1267/ahc.17011 CrossRefPubMedPubMedCentral

22.

Iwabuchi E, Miki Y, Kanai A et al (2018) The interaction between carcinoembryonic antigen-related cell adhesion molecule 6 and HER2 is associated with therapeutic efficacy of trastuzumab in breast cancer. J Pathol 246:379–389. https://doi.org/10.1002/path.5148 CrossRefPubMed

23.

Miki Y, Iwabuchi E, Ono K et al (2018) Exploring protein–protein interaction in the study of hormone-dependent cancers. Int J Mol Sci 19:3173. https://doi.org/10.3390/ijms19103173 CrossRefPubMedCentral

24.

Rahim S, Üren A (2011) A real-time electrical impedance based technique to measure invasion of endothelial cell monolayer by cancer cells. J Vis Exp e2792. https://doi.org/10.3791/2792 CrossRef

25.

Yao P-L, Chen LP, Dobrzański TP et al (2015) Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms. Oncotarget 6:36319–36337. https://doi.org/10.18632/oncotarget.5415 CrossRefPubMedPubMedCentral

26.

Prat A, Perou CM (2009) Mammary development meets cancer genomics. Nat Med 15:842–844. https://doi.org/10.1038/nm0809-842 CrossRefPubMed

27.

Kalluri R, Weinberg R (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428. https://doi.org/10.1172/JCI39104.1420 CrossRefPubMedPubMedCentral

28.

Craene B, De Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13:97–110. https://doi.org/10.1038/nrc3447 CrossRefPubMed

29.

Bronsert P, Enderle-Ammour K, Bader M et al (2014) Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface. J Pathol 234:410–422. https://doi.org/10.1002/path.4416 CrossRefPubMed

30.

Chen J, Li Q, An Y et al (2013) CEACAM6 induces epithelial-mesenchymal transition and mediates invasion and metastasis in pancreatic cancer. Int J Oncol 43:877–885. doi:https://doi.org/10.3892/ijo.2013.2015 CrossRefPubMed

31.

Zang M, Zhang B, Zhang Y et al (2014) CEACAM6 promotes gastric cancer invasion and metastasis by inducing epithelial-mesenchymal transition via PI3K/AKT signaling pathway. PLoS ONE 9:1–10. https://doi.org/10.1371/journal.pone.0112908 CrossRef

32.

Ihnen M, Kilic E, Köhler N et al (2011) Protein expression analysis of ALCAM and CEACAM6 in breast cancer metastases reveals significantly increased ALCAM expression in metastases of the skin. J Clin Pathol 64:146–152. https://doi.org/10.1136/jcp.2010.082602 CrossRefPubMed

33.

Jiang M, Xu X, Bi Y et al (2014) Systemic inflammation promotes lung metastasis via E-selectin upregulation in mouse breast cancer model. Cancer Biol Ther 15:789–796. https://doi.org/10.4161/cbt.28552 CrossRefPubMedPubMedCentral

34.

Chi J-T, Chang HY, Haraldsen G et al (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci USA 100:10623–10628. https://doi.org/10.1073/pnas.1434429100 CrossRefPubMedPubMedCentral

35.

Duxbury MS, Ito H, Ashley SW, Whang EE (2004) c-Src-dependent cross-talk between CEACAM6 and αvβ3integrin enhances pancreatic adenocarcinoma cell adhesion to extracellular matrix components. Biochem Biophys Res Commun 317:133–141. https://doi.org/10.1016/j.bbrc.2004.03.018 CrossRefPubMed

36.

Zhang XH, Jin X, Malladi S et al (2013) Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154:1060–1073. doi:https://doi.org/10.1016/j.cell.2013.07.036.Selection CrossRefPubMedPubMedCentral

37.

Brooks SC, Locke ER, Soule HD (1973) Estrogen receptor in a human cell line (MCF-7) from breast carcinoma. J Biol Chem 248:6251–6253PubMed

38.

Engel LW, Young NA, Tralka TS et al (1978) Establishment and characterization of three new continuous cell lines derived from human breast carcinomas. Cancer Res 38:3352–3364PubMed

39.

Kubota T, Kubouchi K, Koh J et al (1983) Human breast carcinoma (MCF-7) serially transplanted into nude mice. Jpn J Surg 13:381–384CrossRefPubMed

40.

Zhan Q, Fan S, Bae I et al (1994) Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene 9:3743–3751PubMed

41.

Huovinen M, Loikkanen J, Myllynen P et al (2011) Characterization of human breast cancer cell lines for the studies on p53 in chemical carcinogenesis. Toxicol In Vitro 25:1007–1017. https://doi.org/10.1016/j.tiv.2011.03.018 CrossRefPubMed

Title: Co-expression of carcinoembryonic antigen-related cell adhesion molecule 6 and 8 inhibits proliferation and invasiveness of breast carcinoma cells
Authors: Erina Iwabuchi
Yasuhiro Miki
Yoshiaki Onodera
Yukiko Shibahara
Kiyoshi Takagi
Takashi Suzuki
Takanori Ishida
Hironobu Sasano
Publication date: 01-10-2019
Publisher: Springer Netherlands
Keywords: Metastasis
Breast Cancer
Breast Cancer
Published in: Clinical & Experimental Metastasis / Issue 5/2019
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-019-09981-2

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