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Molecular Cancer
Published in: Molecular Cancer 1/2013

Open Access 01-12-2013 | Research

In triple negative breast tumor cells, PLC-β2 promotes the conversion of CD133high to CD133low phenotype and reduces the CD133-related invasiveness

Authors: Federica Brugnoli, Silvia Grassilli, Manuela Piazzi, Maria Palomba, Ervin Nika, Alberto Bavelloni, Silvano Capitani, Valeria Bertagnolo

Published in: Molecular Cancer | Issue 1/2013

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Abstract

Background

Beyond its possible correlation with stemness of tumor cells, CD133/prominin1 is considered an important marker in breast cancer, since it correlates with tumor size, metastasis and clinical stage of triple-negative breast cancers (TNBC), to date the highest risk breast neoplasia.

Methods

To study the correlation between the levels of CD133 expression and the biology of breast-derived cells, CD133low and CD133high cell subpopulations isolated from triple negative MDA-MB-231 cells were compared in terms of malignant properties and protein expression.

Results

High expression of CD133 characterizes cells with larger adhesion area, lower proliferation rate and reduced migration speed, indicative of a less undifferentiated phenotype. Conversely, when compared with CD133low cells, CD133high cells show higher invasive capability and increased expression of proteins involved in metastasis and drug-resistance of breast tumors. Among the signalling proteins examined, PLC-β2 expression inversely correlates with the levels of CD133 and has a role in inducing the CD133high cells to CD133low cells conversion, suggesting that, in TNBC cells, the de-regulation of this PLC isoform is responsible of the switch from an early to a mature tumoral phenotype also by reducing the expression of CD133.

Conclusions

Since CD133 plays a role in determining the invasiveness of CD133high cells, it may constitute an attractive target to reduce the metastatic potential of TNBC. In addition, our data showing that the forced up-regulation of PLC-β2 counteracts the invasiveness of CD133-positive MDA-MB-231 cells might contribute to identify unexplored key steps responsible for the TNBC high malignancy, to be considered for potential therapeutic strategies.
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Literature
1.
Eroles P, Bosch A, Pérez-Fidalgo A, Lluch A: Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev. 2012, 38: 698-707. 10.1016/j.ctrv.2011.11.005CrossRefPubMed
2.
Rakha EA, El-Sayed ME, Reis-Filho J, Ellis IO: Patho-biological aspects of basal-like breast cancer. Breast Cancer Res Treat. 2009, 113: 411-422. 10.1007/s10549-008-9952-1CrossRefPubMed
3.
Zhao P, Lu Y, Jiang X, Li X: Clinicopathological significance and prognostic value of CD133 expression in triple-negative breast carcinoma. Cancer Sci. 2011, 102: 1107-1111. 10.1111/j.1349-7006.2011.01894.xCrossRefPubMed
4.
Mizrak D, Brittan M, Alison M: CD133: molecule of the moment. J Pathol. 2008, 214: 3-9. 10.1002/path.2283CrossRefPubMed
5.
Kemper K, Sprick MR, De Bree M, Scopelliti A, Vermeulen L, Vermeulen L, Hoek M, Zeilstra J, Pals ST, Mehmet H, Stassi G, Medema JP: The AC133 Epitope, but not the CD133 Protein, Is Lost upon Cancer Stem Cell Differentiation. Cancer Res. 2010, 70: 719-729. 10.1158/0008-5472.CAN-09-1820CrossRefPubMed
6.
Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, Zabinski RF, Sutherland MK, Gerber HP, Van Orden KL, Moore PA, Ruben SM, Carter PJ: CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer. 2008, 99: 100-109. 10.1038/sj.bjc.6604437PubMedCentralCrossRefPubMed
7.
Pohl A, El-Khoueiry A, Yang D, Zhang W, Lurje G, Ning Y, Winder T, Hu-Lieskoven S, Iqbal S, Danenberg KD, Kahn M, Teo JL, Shriki J, Stebbing J, Lenz HJ: Pharmacogenetic profiling of CD133 is associated with response rate (RR) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), treated with bevacizumab-based chemotherapy. Pharmacogenomics J. 2013, 13: 173-180. 10.1038/tpj.2011.61PubMedCentralCrossRefPubMed
8.
Pallini R, Ricci-Vitiani L, Montano N, Mollinari C, Biffoni M, Cenci T, Pierconti F, Martini M, De Maria R, Larocca LM: Expression of the stem cell marker CD133 in recurrent Glioblastoma and its value for prognosis. Cancer. 2011, 117: 162-174. 10.1002/cncr.25581CrossRefPubMed
9.
Campos B, Herold-Mende CC: Insight into the complex regulation of CD133 in glioma. Int J Cancer. 2011, 128: 501-510. 10.1002/ijc.25687CrossRefPubMed
10.
Sun J, Zhang C, Liu G, Liu H, Zhou C, Lu Y, Zhou C, Yuan L, Li X: A novel mouse CD133 binding-peptide screened by phage display inhibits cancer cell motility in vitro. Clin Exp Metastasis. 2012, 29: 185-196. 10.1007/s10585-011-9440-6CrossRefPubMed
11.
Rappa G, Fodstad O, Lorico A: The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells. 2008, 26: 3008-3017. 10.1634/stemcells.2008-0601PubMedCentralCrossRefPubMed
12.
Di Bonito M, Cantile M, Collina F, Scognamiglio G, Cerrone M, Cerrone M, La Mantia E, Barbato A, Liguori G, Botti G: Overexpression of cell cycle progression inhibitor geminin is associated with tumor stem-like phenotype of triple-negative breast cancer. J Breast Cancer. 2012, 15: 162-171. 10.4048/jbc.2012.15.2.162PubMedCentralCrossRefPubMed
13.
Schwab LP, Peacock DL, Majumdar D, Ingels JF, Jensen LC, Smith KD, Cushing RC, Seagroves TN: Hypoxia-inducible factor 1a promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res. 2012, 14: R6- 10.1186/bcr3087PubMedCentralCrossRefPubMed
14.
Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL: Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas. Proc Natl Acad Sci U S A. 1991, 88: 10435-10439. 10.1073/pnas.88.23.10435PubMedCentralCrossRefPubMed
15.
Leung DW, Tompkins C, Brewer J, Ball A, Coon M, Valerie M, David W, Jack W, Singeret AL: Phospholipase C delta-4 overexpression upregulates ErbB1/2 expression, Erk signaling pathway, and proliferation in MCF-7 cells. Mol Cancer. 2004, 3: 15-doi: 10.1186/1476-4598-3-15PubMedCentralCrossRefPubMed
16.
Bertagnolo V, Benedusi M, Brugnoli F, Lanuti P, Marchisio M, Querzoli P, Capitani S: Phospholipase C-beta 2 promotes mitosis and migration of human breast cancer-derived cells. Carcinogenesis. 2007, 28: 1638-1645. 10.1093/carcin/bgm078CrossRefPubMed
17.
Rebecchi MJ, Raghubir A, Scarlata S, Hartenstine MJ, Brown T, Stallings JD: Expression and function of phospholipase C in breast carcinoma. Adv Enzyme Regul. 2009, 49: 59-73. 10.1016/j.advenzreg.2009.01.009CrossRefPubMed
18.
Bertagnolo V, Benedusi M, Querzoli P, Pedriali M, Magri E, Brugnoli F, Capitani S: PLC-beta2 is highly expressed in breast cancer and is associated with a poor outcome: a study on tissue microarrays. Int J Oncol. 2006, 28: 863-872.PubMed
19.
Peng Z, Weber JC, Han Z, Shen R, Zhou W, Scott JR, Chan MW, Lin HJ: Dichotomy effects of Akt signaling in breast cancer. Mol Cancer. 2012, 11: 61- 10.1186/1476-4598-11-61PubMedCentralCrossRefPubMed
20.
Sartelet H, Imbriglio T, Nyalendo C, Haddad E, Annabi B, Duval M, Fetni R, Victor K, Alexendrov L, Sinnett D, Fabre M, Vassal G: CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathway. Histopathology. 2012, 60: 1144-1155. 10.1111/j.1365-2559.2012.04191.xCrossRefPubMed
21.
Lattanzio R, Marchisio M, La Sorda R, Tinari N, Falasca M, Alberti S, Miscia S, Ercolani C, Di Benedetto A, Perracchio L, Melucci E, Iacobelli S, Mottolese M, Natali PG, Piantelli M: Overexpression of activated phospholipase Cγ1 is a risk factor for distant metastases in T1-T2, N0 breast cancer patients undergoing adjuvant chemotherapy. Int J Cancer. 2013, 132: 1022-1031. 10.1002/ijc.27751CrossRefPubMed
22.
Li DQ, Wang L, Fei F, Hou YF, Luo JM, Wei-Chen , Zeng R, Wu J, Lu JS, Di GH, Ou ZL, Xia QC, Shen ZZ, Shao ZM: Identification of breast cancer metastasis-associated proteins in an isogenic tumor metastasis model using two-dimensional gel electrophoresis and liquid chromatography-ion trap-mass spectrometry. Proteomics. 2006, 6: 352-3368.
23.
Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L: Brca1 breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 2008, 10: R10- 10.1186/bcr1855PubMedCentralCrossRefPubMed
24.
25.
Anderson LH, Boulanger CA, Smith GH, Carmeliet P, Watson CJ: Stem cell marker prominin-1 regulates branching morphogenesis, but not regenerative capacity, in the mammary gland. Dev Dyn. 2011, 240: 674-681. 10.1002/dvdy.22539PubMedCentralCrossRefPubMed
26.
Liu Q, Li JG, Zheng XY, Jin F, Dong HT: Expression of CD133, PAX2, ESA, and GPR30 in invasive ductal breast carcinomas. Chin Med J (Engl). 2009, 122: 2763-2769.
27.
Aomatsu N, Yashiro M, Kashiwagi S, Takashima T, Ishikawa T, Ohsawa M, Wakasa K, Hirakawa K: CD133 is a useful surrogate marker for predicting chemosensitivity to neoadjuvant chemotherapy in breast cancer. PLoS One. 2012, 7: e45865- 10.1371/journal.pone.0045865PubMedCentralCrossRefPubMed
28.
Currie MJ, Beardsley BE, Harris GC, Gunningham SP, Dachs GU, Dijkstra B, Morrin HR, Wells JE, Robinson BA: Immunohistochemical analysis of cancer stem cell markersin invasive breast carcinoma and associated ductal carcinoma in situ: relationships with markers of tumor hypoxia and microvascularity. Hum Pathol. 2013, 44: 402-411. 10.1016/j.humpath.2012.06.004CrossRefPubMed
29.
Liu TJ, Sun BC, Zhao XL, Zhao XM, Sun T, Gu Q, Yao Z, Dong XY, Zhao N, Liu N: CD133+ cells with cancer stem cell characteristics associates with vasculogenic mimicry in triple-negative breast cancer. Oncogene. 2013, 32: 544-553. 10.1038/onc.2012.85CrossRefPubMed
30.
Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Mildew T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D'Angelica M, Kemeny N, Lyden D, Rafii S: CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumors. J Clin Invest. 2008, 118: 2111-2120.PubMedCentralPubMed
31.
Castillo-Pichardo L, Cubano LA, Dharmawardhane S: Dietary grape polyphenol resveratrol increases mammary tumor growth and metastasis in immunocompromised mice. BMC Complement Altern Med. 2013, 13: 6- 10.1186/1472-6882-13-6PubMedCentralCrossRefPubMed
32.
33.
Swaminathan SK, Olin MR, Forster CL, Cruz KS, Panyam J, Ohlfest JR: Identification of a novel monoclonal antibody recognizing CD133. J Immunol Methods. 2010, 361: 110-115. 10.1016/j.jim.2010.07.007CrossRefPubMed
34.
Hermansen SK, Christensen KG, Jensen SS, Kristensen BW: Inconsistent immunohistochemical expression patterns of four different CD133 antibody clones in glioblastoma. J Histochem Cytochem. 2011, 59: 391-407. 10.1369/0022155411400867PubMedCentralCrossRefPubMed
35.
Hodgkinson VC, Agarwal V, ELFadl D, Fox JN, McManus PL, Mahapatra TK, Kneeshaw PJ, Drew PJ, Lind MJ, Cawkwell L: Pilot and feasibility study: comparative proteomic analysis by 2-DE MALDI TOF/TOF MS reveals 14-3-3 proteins as putative biomarkers of response to neoadjuvant chemotherapy in ER-positive breast cancer. J Proteomics. 2012, 75: 2745-2752. 10.1016/j.jprot.2012.03.049CrossRefPubMed
36.
Vercoutter-Edouart AS, Lemoine J, Le Bourhis X, Louis H, Boilly B, Nurcombe V, Révillion F, Peyrat JP, Hondermarck H: Proteomic analysis reveals that 14-3-3sigma is down-regulated in human breast cancer cells. Cancer Res. 2001, 61: 76-80.PubMed
37.
DeAngelis JT, Li Y, Mitchell N, Wilson L, Kim H, Tollefsbol TO: 2D difference gel electrophoresis analysis of different time points during the course of neoplastic transformation of human mammary epithelial cells. J Proteome Res. 2011, 10: 447-458. 10.1021/pr100533kPubMedCentralCrossRefPubMed
38.
Chou RH, Wen HC, Liang WG, Lin SC, Yuan HW, Wu CW, Chan WS: Suppression of the invasion and migration of cancer cells by SERPINB family genes and their derived peptides. Oncol Rep. 2012, 27: 238-245.PubMed
39.
Hayden A, Johnson PW, Packham G, Crabb SJ: S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition. Breast Cancer Res Treat. 2011, 127: 109-119. 10.1007/s10549-010-0982-0CrossRefPubMed
40.
Yerlikaya A, DoKudur H: Investigation of the eIF2alpha phosphorylation mechanism in response to proteasome inhibition in melanoma and breast cancer cells. Mol Biol. 2010, 44: 859-866.CrossRef
41.
Switzer CH, Glynn SA, Ridnour LA, Cheng RY, Vitek MP, Ambs S, Wink DA: Nitric oxide and protein phosphatase 2A provide novel therapeutic opportunities in ER-negative breast cancer. Trends Pharmacol Sci. 2011, 32: 644-651. 10.1016/j.tips.2011.07.001PubMedCentralCrossRefPubMed
42.
Marchione R, Leibovitch SA, Lenormand JL: The translational factor eIF3f: the ambivalent eIF3 subunit. Cell Mol Life Sci. 2013, In press
43.
44.
Gellekink H, Den Heijer M, Kluijtmans LA, Blom HJ: Effect of genetic variation in the human S-adenosylhomocysteine hydrolase gene on total homocysteine concentrations and risk of recurrent venous thrombosis. Eur J Hum Genet. 2004, 12: 942-948. 10.1038/sj.ejhg.5201237CrossRefPubMed
45.
Liang H, Ding X, Zhou C, Zhang Y, Xu M, Zhang C, Xu L: Knockdown of eukaryotic translation initiation factors 3B (EIF3B) inhibits proliferation and promotes apoptosis in glioblastoma cells. Neurol Sci. 2012, 33: 1057-1062. 10.1007/s10072-011-0894-8CrossRefPubMed
46.
Sala G, Dituri F, Raimondi C, Previdi S, Maffucci T, Mazzoletti M, Rossi C, Iezzi M, Lattanzio R, Piantelli M, Iacobelli S, Broggini M, Falasca M: Phospholipase Cgamma1 is required for metastasis development and progression. Cancer Res. 2008, 68: 10187-10196. 10.1158/0008-5472.CAN-08-1181CrossRefPubMed
47.
Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA, Allan AL: High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med. 2009, 13: 2236-2252. 10.1111/j.1582-4934.2008.00455.xCrossRefPubMed
48.
Bertagnolo V, Grassilli S, Bavelloni A, Brugnoli F, Piazzi M, Candiano G, Petretto A, Benedusi M, Capitani S: Vav1 modulates protein expression during ATRA-induced maturation of APL-derived promyelocytes: a proteomic-based analysis. J Proteome Res. 2008, 7: 3729-3736. 10.1021/pr7008719CrossRefPubMed
49.
Bavelloni A, Faenza I, Cioffi G, Piazzi M, Parisi D, Matic I, Maraldi NM, Cocco L: Proteomic-based analysis of nuclear signaling: PLCbeta1 affects the expression of the splicing factor SRp20 in Friend erythroleukemia cells. Proteomics. 2006, 6: 5725-5734. 10.1002/pmic.200600318CrossRefPubMed
50.
Bertagnolo V, Nika E, Brugnoli F, Bonora M, Grassilli S, Pinton P, Capitani S: Vav1 is a crucial molecule in monocytic/macrophagic differentiation of myeloid leukemia-derived cells. Cell Tissue Res. 2011, 345: 163-175. 10.1007/s00441-011-1195-5CrossRefPubMed
51.
Stander XX, Stander BA, Joubert AM: In vitro effects of an in silico-modelled 17β-estradiol derivative in combination with dichloroacetic acid on MCF-7 and MCF-12A cells. Cell Prolif. 2011, 44: 567-581. 10.1111/j.1365-2184.2011.00789.xCrossRefPubMed
52.
Mandel K, Seidl D, Rades D, Lehnert H, Gieseler F, Hass R, Ungefroren H: Characterization of spontaneous and TGF-β-induced cell motility of primary human normal and neoplastic mammary cells in vitro using novel real-time technology. PLoS One. 2013, 8: e56591-doi:10.1371PubMedCentralCrossRefPubMed
Metadata
Title
In triple negative breast tumor cells, PLC-β2 promotes the conversion of CD133high to CD133low phenotype and reduces the CD133-related invasiveness
Authors
Federica Brugnoli
Silvia Grassilli
Manuela Piazzi
Maria Palomba
Ervin Nika
Alberto Bavelloni
Silvano Capitani
Valeria Bertagnolo
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2013
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-12-165

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