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Tumor Biology
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

ABCG2 is a potential marker of tumor-initiating cells in breast cancer

Authors: Renata Danielle Sicchieri, Willian Abraham da Silveira, Larissa Raquel Mouro Mandarano, Tatiane Mendes Gonçalves de Oliveira, Hélio Humberto Angotti Carrara, Valdair Francisco Muglia, Jurandyr Moreira de Andrade, Daniel Guimarães Tiezzi

Published in: Tumor Biology | Issue 12/2015

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Abstract

The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2+ cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R 2 = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2+ cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2Up breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2+ cells in breast carcinomas is a marker of resistance to chemotherapy, and based on in vitro assays and the genetic profile, we show, for the first time, that ABCG2 protein can be used as an independent marker for TIC identification in breast cancer.
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Literature
1.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.CrossRefPubMedPubMedCentral
2.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. Aldh1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.CrossRefPubMedPubMedCentral
3.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.CrossRefPubMed
4.
Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle. 2007;6:2332–8.CrossRefPubMed
5.
Charafe-Jauffret E, Ginestier C, Iovino F, Tarpin C, Diebel M, Esterni B, et al. Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res. 2010;16:45–55.CrossRefPubMed
6.
Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36 Suppl 1:59–72.CrossRefPubMed
7.
Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H. Prevalence of cd44+/cd24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res. 2005;11:1154–9.PubMed
8.
Beriwal S, Schwartz GF, Komarnicky L, Garcia-Young JA. Breast-conserving therapy after neoadjuvant chemotherapy: long-term results. Breast J. 2006;12:159–64.CrossRefPubMed
9.
Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10:R25.CrossRefPubMedPubMedCentral
10.
Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from national surgical adjuvant breast and bowel project b-18. J Clin Oncol. 1997;15:2483–93.CrossRefPubMed
11.
Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–85.CrossRefPubMed
12.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.CrossRefPubMed
13.
Zhou L, Jiang Y, Yan T, Di G, Shen Z, Shao Z, et al. The prognostic role of cancer stem cells in breast cancer: a meta-analysis of published literatures. Breast Cancer Res Treat. 2010;122:795–801.CrossRefPubMed
14.
Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65:5506–11.CrossRefPubMed
15.
Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, et al. A multidrug resistance transporter from human mcf-7 breast cancer cells. Proc Natl Acad Sci U S A. 1998;95:15665–70.CrossRefPubMedPubMedCentral
16.
Grimshaw MJ, Cooper L, Papazisis K, Coleman JA, Bohnenkamp HR, Chiapero-Stanke L, et al. Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cells. Breast Cancer Res. 2008;10:R52.CrossRefPubMedPubMedCentral
17.
Avital I, Stojadinovic A, Wang H, Mannion C, Cho WC, Wang J, et al. Isolation of stem cells using spheroids from fresh surgical specimen: an analytic mini-review. Cancer Genomics Proteomics. 2014;11:57–65.PubMed
18.
Pommier SJ, Hernandez A, Han E, Massimino K, Muller P, Diggs B, et al. Fresh surgical specimens yield breast stem/progenitor cells and reveal their oncogenic abnormalities. Ann Surg Oncol. 2012;19:527–35.CrossRefPubMed
19.
Abrial SC, Penault-Llorca F, Delva R, Bougnoux P, Leduc B, Mouret-Reynier MA, et al. High prognostic significance of residual disease after neoadjuvant chemotherapy: a retrospective study in 710 patients with operable breast cancer. Breast Cancer Res Treat. 2005;94:255–63.CrossRefPubMed
20.
Murphy PM. Chemokines and the molecular basis of cancer metastasis. N Engl J Med. 2001;345:833–5.CrossRefPubMed
21.
Benderra Z, Faussat AM, Sayada L, Perrot JY, Chaoui D, Marie JP, et al. Breast cancer resistance protein and p-glycoprotein in 149 adult acute myeloid leukemias. Clin Cancer Res. 2004;10:7896–902.CrossRefPubMed
22.
Diestra JE, Scheffer GL, Catala I, Maliepaard M, Schellens JH, Scheper RJ, et al. Frequent expression of the multi-drug resistance-associated protein bcrp/mxr/abcp/abcg2 in human tumours detected by the bxp-21 monoclonal antibody in paraffin-embedded material. J Pathol. 2002;198:213–9.CrossRefPubMed
23.
Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the atp binding cassette (abc) family: an overview. Adv Drug Deliv Rev. 2003;55:3–29.CrossRefPubMed
24.
Blot E, Laberge-Le Couteulx S, Jamali H, Cornic M, Guillemet C, Duval C, et al. Cxcr4 membrane expression in node-negative breast cancer. Breast J. 2008;14:268–74.CrossRefPubMed
25.
Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP, et al. A possible role for cxcr4 and its ligand, the cxc chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol. 2001;167:4747–57.CrossRefPubMed
26.
Liang Z, Yoon Y, Votaw J, Goodman MM, Williams L, Shim H. Silencing of cxcr4 blocks breast cancer metastasis. Cancer Res. 2005;65:967–71.PubMedPubMedCentral
27.
Porcile C, Bajetto A, Barbero S, Pirani P, Schettini G. Cxcr4 activation induces epidermal growth factor receptor transactivation in an ovarian cancer cell line. Ann N Y Acad Sci. 2004;1030:162–9.CrossRefPubMed
28.
Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, Piwnica-Worms D, et al. Cxcr4 regulates growth of both primary and metastatic breast cancer. Cancer Res. 2004;64:8604–12.CrossRefPubMed
29.
Miyake T, Nakayama T, Naoi Y, Yamamoto N, Otani Y, Kim SJ, et al. Gstp1 expression predicts poor pathological complete response to neoadjuvant chemotherapy in er-negative breast cancer. Cancer Sci. 2012;103:913–20.CrossRefPubMed
30.
Team RC. R: a language and environment for statistical computing. Vienna: Foundation for Statistical Computing; 2014.
31.
Gautier L, Cope L, Bolstad BM, Irizarry RA. Affy–analysis of affymetrix genechip data at the probe level. Bioinformatics. 2004;20:307–15.CrossRefPubMed
32.
33.
34.
Smyth GK. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3, Article3.CrossRefPubMed
35.
36.
Safran M, Dalah I, Alexander J, Rosen N, Iny Stein T, Shmoish M, et al. Genecards version 3: the human gene integrator. Database (Oxford). 2010;2010, baq020.CrossRef
37.
38.
Chioni AM, Brackenbury WJ, Calhoun JD, Isom LL, Djamgoz MB. A novel adhesion molecule in human breast cancer cells: voltage-gated Na+ channel beta1 subunit. Int J Biochem Cell Biol. 2009;41:1216–27.CrossRefPubMed
39.
Krupp M, Weinmann A, Galle PR, Teufel A. Actin binding lim protein 3 (ablim3). Int J Mol Med. 2006;17:129–33.PubMed
40.
41.
42.
Reinhold WC, Erliandri I, Liu H, Zoppoli G, Pommier Y, Larionov V. Identification of a predominant co-regulation among kinetochore genes, prospective regulatory elements, and association with genomic instability. PLoS One. 2011;6, e25991.CrossRefPubMedPubMedCentral
43.
44.
Wascher RA, Bostick PJ, Huynh KT, Turner R, Qi K, Giuliano AE, et al. Detection of mage-a3 in breast cancer patients’ sentinel lymph nodes. Br J Cancer. 2001;85:1340–6.CrossRefPubMedPubMedCentral
45.
Wong PP, Yeoh CC, Ahmad AS, Chelala C, Gillett C, Speirs V, et al. Identification of magea antigens as causal players in the development of tamoxifen-resistant breast cancer. Oncogene. 2014;33:4579–88.CrossRefPubMedPubMedCentral
46.
Hofmann HS, Hansen G, Richter G, Taege C, Simm A, Silber RE, et al. Matrix metalloproteinase-12 expression correlates with local recurrence and metastatic disease in non-small cell lung cancer patients. Clin Cancer Res. 2005;11:1086–92.PubMed
47.
Hu Y, Xing J, Wang L, Huang M, Guo X, Chen L, et al. Rgs22, a novel cancer/testis antigen, inhibits epithelial cell invasion and metastasis. Clin Exp Metastasis. 2011;28:541–9.CrossRefPubMed
48.
Green S, Walter P, Kumar V, Krust A, Bornert JM, Argos P, et al. Human oestrogen receptor cdna: sequence, expression and homology to v-erb-a. Nature. 1986;320:134–9.CrossRefPubMed
49.
Yamamoto KK, Pousette A, Chow P, Wilson H, el Shami S, French CK. Isolation of a cdna encoding a human serum marker for acute pancreatitis. Identification of pancreas-specific protein as pancreatic procarboxypeptidase b. J Biol Chem. 1992;267:2575–81.PubMed
50.
51.
52.
53.
54.
Zinzi L, Contino M, Cantore M, Capparelli E, Leopoldo M, Colabufo NA. Abc transporters in cscs membranes as a novel target for treating tumor relapse. Front Pharmacol. 2014;5:163.CrossRefPubMedPubMedCentral
55.
Scharenberg CW, Harkey MA, Torok-Storb B. The abcg2 transporter is an efficient hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood. 2002;99:507–12.CrossRefPubMed
56.
Tiezzi DG, Valejo FA, Marana HR, Carrara HH, Benevides L, Antonio HM, Sicchieri RD, Milanezi CM, Silva JS, de Andrade JM. Cd44(+)/cd24 (−) cells and lymph node metastasis in stage i and ii invasive ductal carcinoma of the breast. Med Oncol. 2011;29(3):1479–85.
57.
Honeth G, Bendahl PO, Ringner M, Saal LH, Gruvberger-Saal SK, Lovgren K, et al. The cd44+/cd24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10:R53.CrossRefPubMedPubMedCentral
58.
Krishnamurthy P, Schuetz JD. The role of abcg2 and abcb6 in porphyrin metabolism and cell survival. Curr Pharm Biotechnol. 2011;12:647–55.CrossRefPubMed
59.
Natarajan K, Xie Y, Baer MR, Ross DD. Role of breast cancer resistance protein (bcrp/abcg2) in cancer drug resistance. Biochem Pharmacol. 2012;83:1084–103.CrossRefPubMedPubMedCentral
60.
Klopp AH, Lacerda L, Gupta A, Debeb BG, Solley T, Li L, et al. Mesenchymal stem cells promote mammosphere formation and decrease e-cadherin in normal and malignant breast cells. PLoS One. 2010;5, e12180.CrossRefPubMedPubMedCentral
61.
Yan XL, Fu CJ, Chen L, Qin JH, Zeng Q, Yuan HF, et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via egf/egfr/akt pathway. Breast Cancer Res Treat. 2012;132:153–64.CrossRefPubMed
Metadata
Title
ABCG2 is a potential marker of tumor-initiating cells in breast cancer
Authors
Renata Danielle Sicchieri
Willian Abraham da Silveira
Larissa Raquel Mouro Mandarano
Tatiane Mendes Gonçalves de Oliveira
Hélio Humberto Angotti Carrara
Valdair Francisco Muglia
Jurandyr Moreira de Andrade
Daniel Guimarães Tiezzi
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3647-0

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