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Breast Cancer Research
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research article

Low expression of galectin-3 is associated with poor survival in node-positive breast cancers and mesenchymal phenotype in breast cancer stem cells

Authors: Matthias Ilmer, Nachman Mazurek, Michael Z. Gilcrease, James C. Byrd, Wendy A. Woodward, Thomas A. Buchholz, Kim Acklin, Karen Ramirez, Margarete Hafley, Eckhard Alt, Jody Vykoukal, Robert S. Bresalier

Published in: Breast Cancer Research | Issue 1/2016

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Abstract

Background

Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness.

Method

To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression.

Results

Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3negative BCSCs were associated with enhanced tumorigenicity in orthotopic mouse models.

Conclusions

Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.
Appendix
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Literature
1.
Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, Zackrisson S, Cardoso F. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v8–v30.CrossRefPubMed
2.
Al-Ejeh F, Smart CE, Morrison BJ, Chenevix-Trench G, López JA, Lakhani SR, Brown MP, Khanna KK. Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis. 2011;32:650–8.CrossRefPubMed
3.
Takebe N, Warren RQ, Ivy SP. Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res. 2011;13:211.CrossRefPubMedPubMedCentral
4.
Valent P, Bonnet D, de Maria R, Lapidot T, Copland M, Melo JV, Chomienne C, Ishikawa F, Schuringa JJ, Stassi G, Huntly B, Herrmann H, Soulier J, Roesch A, Schuurhuis GJ, Wöhrer S, Arock M, Zuber J, Cerny-Reiterer S, Johnsen HE, Andreeff M, Eaves C. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer. 2012;12:767–75.CrossRefPubMed
5.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.CrossRefPubMedPubMedCentral
6.
Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2014;2:78–91.CrossRef
7.
Spike BT, Engle DD, Lin JC, Cheung SK, La J, Wahl GM. A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer. Cell Stem Cell. 2012;10:183–97.CrossRefPubMedPubMedCentral
8.
Devarajan E, Song Y-H, Krishnappa S, Alt E. Epithelial-mesenchymal transition in breast cancer lines is mediated through PDGF-D released by tissue-resident stem cells. Int J Cancer. 2012;131:1023–31.CrossRefPubMed
9.
Scheel C, Eaton EN, Li SH-J, Chaffer CL, Reinhardt F, Kah K-J, Bell G, Guo W, Rubin J, Richardson AL, Weinberg RA. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011;145:926–40.CrossRefPubMedPubMedCentral
10.
Korkaya H, Kim G-I, Davis A, Malik F, Henry NL, Ithimakin S, Quraishi AA, Tawakkol N, D'Angelo R, Paulson AK, Chung S, Luther T, Paholak HJ, Liu S, Hassan KA, Zen Q, Clouthier SG, Wicha MS. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–84.CrossRefPubMedPubMedCentral
11.
Mazurek N, Sun YJ, Price JE, Ramdas L, Schober W, Nangia-Makker P, Byrd JC, Raz A, Bresalier RS. Phosphorylation of galectin-3 contributes to malignant transformation of human epithelial cells via modulation of unique sets of genes. Cancer Res. 2005;65:10767–75.CrossRefPubMed
12.
Mazurek N, Byrd JC, Sun Y, Ueno S, Bresalier RS. A galectin-3 sequence polymorphism confers TRAIL sensitivity to human breast cancer cells. Cancer. 2011;117:4375–80.CrossRefPubMedPubMedCentral
13.
Shekhar M, Nangia-Makker P, Tait L, Miller F. Alterations in galectin-3 expression and distribution correlate with breast cancer progression. Am J Pathol. 2004;165:1931–41.CrossRefPubMedPubMedCentral
14.
Sanchez-Ruderisch H, Detjen KM, Welzel M, André S, Fischer C, Gabius H-J, Rosewicz S. Galectin-1 sensitizes carcinoma cells to anoikis via the fibronectin receptor α5β1-integrin. Cell Death Differ. 2011;18:806–16.CrossRefPubMed
15.
Chung L-Y, Tang S-J, Wu Y-C, Sun G-H, Liu H-Y, Sun K-H. Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with β-catenin. Oncotarget. 2015;6:4936–52.CrossRefPubMed
16.
Zhang H, Luo M, Liang X, Wang D, Gu X, Duan C, Gu H, Chen G, Zhao X, Zhao Z, Liu C. Galectin-3 as a marker and potential therapeutic target in breast cancer. PLoS One. 2014;9:e103482.CrossRefPubMedPubMedCentral
17.
Lev DC, Kiriakova G, Price JE. Selection of more aggressive variants of the gI101A human breast cancer cell line: a model for analyzing the metastatic phenotype of breast cancer. Clin Exp Metastasis. 2003;20:515–23.CrossRefPubMed
18.
Mazurek N, Byrd JC, Sun Y, Hafley M, Ramirez K, Burks J, Bresalier RS. Cell-surface galectin-3 confers resistance to TRAIL by impeding trafficking of death receptors in metastatic colon adenocarcinoma cells. Cell Death Differ. 2012;1:523–33.CrossRef
19.
Ilmer M, Boiles AR, Regel I, Yokoi K, Michalski CW, Wistuba II, Rodriguez J, Alt E, Vykoukal J. RSPO2 enhances canonical Wnt signaling to confer stemness-associated traits to susceptible pancreatic cancer cells. Cancer Res. 2015;75:1883–96.CrossRefPubMed
20.
Morrissey JJ, Raney S. A metastatic breast tumor cell line, GI-101A, is estrogen receptor positive and responsive to estrogen but resistant to tamoxifen. Cell Biol Int. 1998;22:413–9.CrossRefPubMed
21.
Silva IA, Bai S, McLean K, Yang K, Griffith K, Thomas D, Ginestier C, Johnston C, Kueck A, Reynolds RK, Wicha MS, Buckanovich RJ. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011;71:3991–4001.CrossRefPubMedPubMedCentral
22.
Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S, Tozzi F, Sceusi E, Zhou Y, Tachibana I, Maru DM, Hawke DH, Rak J, Mani SA, Zweidler-McKay P, Ellis LM. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell. 2013;23:171–85.CrossRefPubMedPubMedCentral
23.
Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003;14:833–42.CrossRefPubMed
24.
DiMeo TA, Anderson K, Phadke P, Fan C, Perou CM, Naber S, Kuperwasser C. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res. 2009;69:5364–73.CrossRefPubMedPubMedCentral
25.
Song S, Mazurek N, Liu C, Sun Y, Ding QQ, Liu K, Hung MC, Bresalier RS. Galectin-3 mediates nuclear beta-catenin accumulation and Wnt signaling in human colon cancer cells by regulation of glycogen synthase kinase-3beta activity. Cancer Res. 2009;69:1343–9.CrossRefPubMedPubMedCentral
26.
Oka N, Nakahara S, Takenaka Y, Fukumori T, Hogan V, Kanayama HO, Yanagawa T, Raz A. Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells. Cancer Res. 2005;65:7546–53.PubMed
27.
Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci. 2001;114:2903–10.PubMed
28.
Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000;6:1389–93.PubMed
29.
Piccolo E, Tinari N, Semeraro D, Traini S, Fichera I, Cumashi A, La Sorda R, Spinella F, Bagnato A, Lattanzio R, D'Egidio M, Di Risio A, Stampolidis P, Piantelli M, Natoli C, Ullrich A, Iacobelli S. LGALS3BP, lectin galactoside-binding soluble 3 binding protein, induces vascular endothelial growth factor in human breast cancer cells and promotes angiogenesis. J Mol Med (Berl). 2013;91:83–94.CrossRef
30.
Song S, Ji B, Ramachandran V, Wang H, Hafley M, Logsdon C, Bresalier RS. Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signaling. PLoS One. 2012;7:e42699.CrossRefPubMedPubMedCentral
31.
Glinsky VV, Kiriakova G, Glinskii OV, Mossine VV, Mawhinney TP, Turk JR, Glinskii AB, Huxley VH, Price JE, Glinsky GV. Synthetic galectin-3 inhibitor increases metastatic cancer cell sensitivity to taxol-induced apoptosis in vitro and in vivo. Neoplasia. 2009;11:901–9.CrossRefPubMedPubMedCentral
32.
Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol. 2012;22:396–403.CrossRefPubMed
33.
Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69:2400–7.CrossRefPubMedPubMedCentral
34.
Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12:R68.CrossRefPubMedPubMedCentral
35.
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006;7:96.CrossRefPubMedPubMedCentral
36.
Murugaesu N, Iravani M, van Weverwijk A, Ivetic A, Johnson DA, Antonopoulos A, Fearns A, Jamal-Hanjani M, Sims D, Fenwick K, Mitsopoulos C, Gao Q, Orr N, Zvelebil M, Haslam SM, Dell A, Yarwood H, Lord CJ, Ashworth A, Isacke CM. An in vivo functional screen identifies ST6GalNAc2 sialyltransferase as a breast cancer metastasis suppressor. Cancer Discov. 2014;4:304–17.CrossRefPubMed
Metadata
Title
Low expression of galectin-3 is associated with poor survival in node-positive breast cancers and mesenchymal phenotype in breast cancer stem cells
Authors
Matthias Ilmer
Nachman Mazurek
Michael Z. Gilcrease
James C. Byrd
Wendy A. Woodward
Thomas A. Buchholz
Kim Acklin
Karen Ramirez
Margarete Hafley
Eckhard Alt
Jody Vykoukal
Robert S. Bresalier
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0757-6

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