Abstract
Background and Objective
Breast cancer stem cells are considered to be a major cause of disease recurrence in breast cancer as they appear to be chemoresistant. Fascin-1 and MAP17 are stem cell markers whose excessive expression in tumors is associated with aggressive tumor phenotypes. The aim of the present study was to investigate the expression patterns of fascin-1 and MAP17 in breast cancer and to assess their clinical significance.
Methods
Expression of fascin-1 and MAP17 was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 127 patients with resectable breast cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival (PFS) was defined as the primary outcome of the present study.
Results
Fascin-1 and MAP17 expression were strongly associated with the presence of triple-negative cancers (p < 0.0001). Tumors displaying high expression of fascin-1 presented correlations with high tumor grade (p = 0.002) and high expression of Ki-67 (p = 0.004). PFS of patients exhibiting high expression of fascin-1 and MAP17 in cancer cells in the first 5 years after surgery was significantly worse than in patients with low expression of the two markers (47.8%, 95% confidence interval [CI] 33–51 vs. 80.5%, 95% CI 47–56; p = 0.012) and independent of other clinicopathological characteristics (hazard ratio 0.171, 95% CI 0.034–0.869; p = 0.033).
Conclusion
Combined expression of fascin-1 and MAP17 in breast cancer cells is associated with a significantly worse 5-year PFS, therefore recognizing a group of patients with high risk for early disease recurrence.
Similar content being viewed by others
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717.
Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14(10):2738–46.
Richman J, Dowsett M. Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat Rev Clin Oncol. 2019;16(5):296–311. https://doi.org/10.1038/s41571-018-0145-5.
Jiang Y, Wells A, Sylakowski K, Clark AM, Ma B. Adult stem cell functioning in the tumor micro-environment. Int J Mol Sci. 2019;20(10):2566. https://doi.org/10.3390/ijms20102566.
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.
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(3):R52.
Marotta LL, Polyak K. Cancer stem cells: a model in the making. Curr Opin Genet Dev. 2009;19(1):44–50.
Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science. 2009;324(5935):1670–3.
Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138(5):822–9.
Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA. 2011;108(4):1397–402.
Gloushankova NA, Zhitnyak IY, Rubtsova SN. Role of epithelial-mesenchymal transition in tumour progression. Biochemistry (Mosc). 2018;83(12):1469–76. https://doi.org/10.1134/S0006297918120052.
Huang FK, Han S, Xing B, Huang J, Liu B, Bordeleau F, et al. Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization. Nat Commun. 2015;17(6):7465. https://doi.org/10.1038/ncomms8465.
Mattila PK, Lappalainen P. Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol. 2008;9(6):446–54.
Claessens MM, Bathe M, Frey E, Bausch AR. Actin-binding proteins sensitively mediate F-actin bundle stiffness. Nat Mater. 2006;5(9):748–53.
Lee HJ, An HJ, Kim TH, Kim G, Kang H, Heo JH, et al. Fascin expression is inversely correlated with breast cancer metastasis suppressor 1 and predicts a worse survival outcome in node-negative breast cancer patients. J Cancer. 2017;8(16):3122–9. https://doi.org/10.7150/jca.22046 (eCollection 2017).
Jayo A, Malboubi M, Antoku S, Chang W, Ortiz-Zapater E, Groen C, et al. Fascin regulates nuclear movement and deformation in migrating cells. Dev Cell. 2016;38(4):371–83. https://doi.org/10.1016/j.devcel.2016.07.021.
Hashimoto Y, Kim DJ, Adams JC. The roles of fascins in health and disease. J Pathol. 2011;224(3):289–300.
Machesky LM, Li A. Fascin: invasive filopodia promoting metastasis. Commun Integr Biol. 2010;3(3):263–70.
Barnawi R, Al-Khaldi S, Majed Sleiman G, Sarkar A, Al-Dhfyan A, Al-Mohanna F, et al. Fascin is critical for the maintenance of breast cancer stem cell pool predominantly via the activation of the Notch self-renewal pathway. Stem Cells. 2016;34(12):2799–813.
Guijarro MV, Link W, Rosado A, Leal JF, Carnero A. MAP17 inhibits Myc-induced apoptosis through PI3K/AKT pathway activation. Carcinogenesis. 2007;28(12):2443–50.
Guijarro MV, Leal JF, Blanco-Aparicio C, Alonso S, Fominaya J, Lleonart M, et al. MAP17 enhances the malignant behavior of tumor cells through ROS increase. Carcinogenesis. 2007;28(10):2096–104.
Chen X, Liao Y, Yu Y, Zhu P, Li J, Qin L, et al. Elevation of MAP17 enhances the malignant behavior of cells via the Akt/mTOR pathway in hepatocellular carcinoma. Oncotarget. 2017;8(54):92589–603.
Perez M, Peinado-Serrano J, Garcia-Heredia JM, Felipe-Abrio I, Tous C, Ferrer I, et al. Efficacy of bortezomib in sarcomas with high levels of MAP17 (PDZK1IP1). Oncotarget. 2016;7(41):67033–46.
Guijarro MV, Leal JF, Fominaya J, Blanco-Aparicio C, Alonso S, Lleonart M, et al. MAP17 overexpression is a common characteristic of carcinomas. Carcinogenesis. 2007;28(8):1646–52.
Carnero A. MAP17 and the double-edged sword of ROS. Biochim Biophys Acta. 2012;1826(1):44–52.
Perez M, Praena-Fernandez JM, Felipe-Abrio B, Lopez-Garcia MA, Lucena-Cacace A, Garcia A, et al. MAP17 and SGLT1 protein expression levels as prognostic markers for cervical tumor patient survival. PLoS One. 2013;8(2):e56169.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Urol. 2005;2(8):416–22.
Gilliland FD, Joste N, Stauber PM, Hunt WC, Rosenberg R, Redlich G, et al. Biologic characteristics of interval and screen-detected breast cancers. J Natl Cancer Inst. 2000;92(9):743–9.
Wang CQ, Li Y, Huang BF, Zhao YM, Yuan H, Guo D, et al. EGFR conjunct FSCN1 as a novel therapeutic strategy in triple-negative breast cancer. Sci Rep. 2017;7(1):15654.
van Cruijsen H, Giaccone G, Hoekman K. Epidermal growth factor receptor and angiogenesis: Opportunities for combined anticancer strategies. Int J Cancer. 2005;117(6):883–8.
Yoder BJ, Tso E, Skacel M, Pettay J, Tarr S, Budd T, et al. The expression of fascin, an actin-bundling motility protein, correlates with hormone receptor-negative breast cancer and a more aggressive clinical course. Clin Cancer Res. 2005;11(1):186–92.
Grothey A, Hashizume R, Sahin AA, McCrea PD. Fascin, an actin-bundling protein associated with cell motility, is upregulated in hormone receptor negative breast cancer. Br J Cancer. 2000;83(7):870–3.
Esnakula AK, Ricks-Santi L, Kwagyan J, Kanaan YM, DeWitty RL, Wilson LL, et al. Strong association of fascin expression with triple negative breast cancer and basal-like phenotype in African-American women. J Clin Pathol. 2014;67(2):153–60.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
Wang CQ, Tang CH, Wang Y, Jin L, Wang Q, Li X, et al. FSCN1 gene polymorphisms: biomarkers for the development and progression of breast cancer. Sci Rep. 2017;7(1):15887.
Jayo A, Parsons M. Fascin: a key regulator of cytoskeletal dynamics. Int J Biochem Cell Biol. 2010;42(10):1614–7.
Li A, Dawson JC, Forero-Vargas M, Spence HJ, Yu X, Konig I, et al. The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion. Curr Biol. 2010;20(4):339–45.
Hashimoto Y, Skacel M, Adams JC. Roles of fascin in human carcinoma motility and signaling: prospects for a novel biomarker? Int J Biochem Cell Biol. 2005;37(9):1787–804.
Al-Alwan M, Olabi S, Ghebeh H, Barhoush E, Tulbah A, Al-Tweigeri T, et al. Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules. PLoS One. 2011;6(11):e27339.
Ghebeh H, Al-Khaldi S, Olabi S, Al-Dhfyan A, Al-Mohanna F, Barnawi R, et al. Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway. Br J Cancer. 2014;111(8):1552–61.
Yao J, Qian CJ, Ye B, Zhao ZQ, Wei J, Liang Y, et al. Signal transducer and activator of transcription 3 signaling upregulates fascin via nuclear factor-kappaB in gastric cancer: Implications in cell invasion and migration. Oncol Lett. 2014;7(3):902–8.
Guijarro MV, Vergel M, Marin JJ, Munoz-Galvan S, Ferrer I, Ramon y Cajal S, et al. p38alpha limits the contribution of MAP17 to cancer progression in breast tumors. Oncogene. 2012;31(41):4447–59.
Garcia-Heredia JM, Lucena-Cacace A, Verdugo-Sivianes EM, Perez M, Carnero A. The cargo protein MAP17 (PDZK1IP1) regulates the cancer stem cell pool activating the Notch pathway by abducting NUMB. Clin Cancer Res. 2017;23(14):3871–83.
Zhang Y, Li B, Ji ZZ, Zheng PS. Notch1 regulates the growth of human colon cancers. Cancer. 2010;116(22):5207–18.
Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.
Ranganathan P, Weaver KL, Capobianco AJ. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 2011;11(5):338–51.
Rodriguez-Rodero S, Fernandez AF, Fernandez-Morera JL, Castro-Santos P, Bayon GF, Ferrero C, et al. DNA methylation signatures identify biologically distinct thyroid cancer subtypes. J Clin Endocrinol Metab. 2013;98(7):2811–21.
Garcia-Heredia JM, Carnero A. The cargo protein MAP17 (PDZK1IP1) regulates the immune microenvironment. Oncotarget. 2017;8(58):98580–97.
Guijarro MV, Castro ME, Romero L, Moneo V, Carnero A. Large scale genetic screen identifies MAP17 as protein bypassing TNF-induced growth arrest. J Cell Biochem. 2007;101(1):112–21.
Munoz-Galvan S, Gutierrez G, Perez M, Carnero A. MAP17 (PDZKIP1) expression determines sensitivity to the proteasomal inhibitor bortezomib by preventing cytoprotective autophagy and NFkappaB activation in breast cancer. Mol Cancer Ther. 2015;14(6):1454–65.
Shao Y, Lv H, Zhong DS, Zhou QH. EGFR-TKI resistance and MAP17 are associated with cancer stem cell like properties. Oncol Lett. 2018;15(5):6655–65.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
ECT, AT, AN, MvF, EP, KK, and GK declare no conflict of interest relating to the content of this study.
Funding
No funding was associated with the present study.
Rights and permissions
About this article
Cite this article
Tampaki, E.C., Tampakis, A., Nonni, A. et al. Combined Fascin-1 and MAP17 Expression in Breast Cancer Identifies Patients with High Risk for Disease Recurrence. Mol Diagn Ther 23, 635–644 (2019). https://doi.org/10.1007/s40291-019-00411-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40291-019-00411-3