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KIF21A regulates breast cancer aggressiveness and is prognostic of patient survival and tumor recurrence

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Abstract

Purpose

Invasion of carcinoma cells into surrounding tissue affects breast cancer staging, influences choice of treatment, and impacts on patient outcome. KIF21A is a member of the kinesin superfamily that has been well-studied in congenital extraocular muscle fibrosis. However, its biological relevance in breast cancer is unknown. This study investigated the functional roles of KIF21A in this malignancy and examined its expression pattern in breast cancer tissue.

Methods

The function of KIF21A in breast carcinoma was studied in vitro by silencing its expression in breast cancer cells and examining the changes in cellular activities. Immunohistochemical staining of breast cancer tissue microarrays was performed to determine the expression patterns of KIF21A.

Results

Knocking down the expression of KIF21A using siRNA in MDA-MB-231 and MCF7 human breast cancer cells resulted in significant decreases in tumor cell migration and invasiveness. This was associated with reduced Patched 1 expression and F-actin microfilaments. Additionally, the number of focal adhesion kinase- and paxillin-associated focal adhesions was increased. Immunohistochemical staining of breast cancer tissue microarrays showed that KIF21A was expressed in both the cytoplasmic and nuclear compartments of carcinoma cells. Predominance of cytoplasmic KIF21A was significantly associated with larger tumors and high grade cancer, and prognostic of cause-specific overall patient survival and breast cancer recurrence.

Conclusion

The data demonstrates that KIF21A is an important regulator of breast cancer aggressiveness and may be useful in refining prognostication of this malignant disease.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  Google Scholar 

  2. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, Znaor A, Bray F (2019) Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144:1941–1953

    CAS  PubMed  Google Scholar 

  3. Koo CY, Sen YP, Bay BH, Yip GW (2008) Targeting heparan sulfate proteoglycans in breast cancer treatment. Recent Pat Anticancer Drug Discov 3:151–158

    CAS  PubMed  Google Scholar 

  4. Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML (2011) Projections of the cost of cancer care in the United States: 2010–2020. J Natl Cancer Inst 103:117–128

    PubMed  PubMed Central  Google Scholar 

  5. Yabroff KR, Lund J, Kepka D, Mariotto A (2011) Economic burden of cancer in the United States: estimates, projections, and future research. Cancer Epidemiol Biomarkers Prev 20:2006–2014

    PubMed  PubMed Central  Google Scholar 

  6. Liu X, Gong H, Huang K (2013) Oncogenic role of kinesin proteins and targeting kinesin therapy. Cancer Sci 104:651–656

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Lucanus AJ, Yip GW (2018) Kinesin superfamily: roles in breast cancer, patient prognosis and therapeutics. Oncogene 37:833–838

    CAS  PubMed  Google Scholar 

  8. Zou JX, Duan Z, Wang J, Sokolov A, Xu J, Chen CZ, Li JJ, Chen HW (2014) Kinesin family deregulation coordinated by bromodomain protein ANCCA and histone methyltransferase MLL for breast cancer cell growth, survival, and tamoxifen resistance. Mol Cancer Res 12:539–549

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Feng YM, Gao G, Zhang F, Chen H, Wan YF, Li XQ (2006) Identification of the differentially expressed genes between primary breast cancer and paired lymph node metastasis through combining mRNA differential display and gene microarray. Zhonghua Yi Xue Za Zhi 86:2749–2755

    CAS  PubMed  Google Scholar 

  10. Feng YM, Wan YF, Li XQ, Cao XC, Li X (2006) Expression and clinical significance of KNSL4 in breast cancer. Ai Zheng 25:744–748

    CAS  PubMed  Google Scholar 

  11. Wang J, Ma S, Ma R, Qu X, Liu W, Lv C, Zhao S, Gong Y (2014) KIF2A silencing inhibits the proliferation and migration of breast cancer cells and correlates with unfavorable prognosis in breast cancer. BMC Cancer 14:461

    PubMed  PubMed Central  Google Scholar 

  12. Corson TW, Huang A, Tsao MS, Gallie BL (2005) KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers. Oncogene 24:4741–4753

    CAS  PubMed  Google Scholar 

  13. Desai J, Velo MP, Yamada K, Overman LM, Engle EC (2012) Spatiotemporal expression pattern of KIF21A during normal embryonic development and in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Gene Expr Patterns 12:180–188

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yamada K, Andrews C, Chan WM, McKeown CA, Magli A, de Berardinis T, Loewenstein A, Lazar M, O’Keefe M, Letson R, London A, Ruttum M, Matsumoto N, Saito N, Morris L, Del Monte M, Johnson RH, Uyama E, Houtman WA, de Vries B, Carlow TJ, Hart BL, Krawiecki N, Shoffner J, Vogel MC, Katowitz J, Goldstein SM, Levin AV, Sener EC, Ozturk BT, Akarsu AN, Brodsky MC, Hanisch F, Cruse RP, Zubcov AA, Robb RM, Roggenkaemper P, Gottlob I, Kowal L, Battu R, Traboulsi EI, Franceschini P, Newlin A, Demer JL, Engle EC (2003) Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 35:318–321

    CAS  PubMed  Google Scholar 

  15. Marszalek JR, Weiner JA, Farlow SJ, Chun J, Goldstein LS (1999) Novel dendritic kinesin sorting identified by different process targeting of two related kinesins: KIF21A and KIF21B. J Cell Biol 145:469–479

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Yamada K, Chan WM, Andrews C, Bosley TM, Sener EC, Zwaan JT, Mullaney PB, Ozturk BT, Akarsu AN, Sabol LJ, Demer JL, Sullivan TJ, Gottlob I, Roggenkaemper P, Mackey DA, De Uzcategui CE, Uzcategui N, Ben-Zeev B, Traboulsi EI, Magli A, de Berardinis T, Gagliardi V, Awasthi-Patney S, Vogel MC, Rizzo JF 3rd, Engle EC (2004) Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3). Invest Ophthalmol Vis Sci 45:2218–2223

    PubMed  Google Scholar 

  17. Sun W, Iijima T, Kano J, Kobayashi H, Li D, Morishita Y, Okubo C, Anami Y, Noguchi M (2008) Frequent aberrant methylation of the promoter region of sterile alpha motif domain 14 in pulmonary adenocarcinoma. Cancer Sci 99:2177–2184

    CAS  PubMed  Google Scholar 

  18. Han Q, Han C, Liao X, Huang K, Wang X, Yu T, Yang C, Li G, Han B, Zhu G, Liu Z, Zhou X, Liu J, Su H, Shang L, Peng T, Ye X (2019) Prognostic value of Kinesin-4 family genes mRNA expression in early-stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy. Cancer Med 8:6487–6502

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Groth-Pedersen L, Aits S, Corcelle-Termeau E, Petersen NH, Nylandsted J, Jaattela M (2012) Identification of cytoskeleton-associated proteins essential for lysosomal stability and survival of human cancer cells. PLoS One 7:e45381

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Iravani O, Bay BH, Yip GW (2017) Silencing HS6ST3 inhibits growth and progression of breast cancer cells through suppressing IGF1R and inducing XAF1. Exp Cell Res 350:380–389

    CAS  PubMed  Google Scholar 

  21. Guo CH, Koo CY, Bay BH, Tan PH, Yip GW (2007) Comparison of the effects of differentially sulphated bovine kidney- and porcine intestine-derived heparan sulphate on breast carcinoma cellular behaviour. Int J Oncol 31:1415–1423

    CAS  PubMed  Google Scholar 

  22. Yu YN, Yip GW, Tan PH, Thike AA, Matsumoto K, Tsujimoto M, Bay BH (2010) Y-box binding protein 1 is up-regulated in proliferative breast cancer and its inhibition deregulates the cell cycle. Int J Oncol 37:483–492

    CAS  PubMed  Google Scholar 

  23. Tan XF, Teo WX, Yip GW (2019) In vitro evaluation of candidate gene targets for cancer therapy. Methods Mol Biol 1974:21–30

    CAS  PubMed  Google Scholar 

  24. Goldman MJ, Craft B, Hastie M, Repecka K, McDade F, Kamath A, Banerjee A, Luo Y, Rogers D, Brooks AN, Zhu J, Haussler D (2020) Visualizing and interpreting cancer genomics data via the Xena platform. Nat Biotechnol 38:675–678

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lo SL, Thike AA, Tan SY, Lim TK, Tan IB, Choo SP, Tan PH, Bay BH, Yip GW (2011) Expression of heparan sulfate in gastric carcinoma and its correlation with clinicopathological features and patient survival. J Clin Pathol 64:153–158

    PubMed  Google Scholar 

  26. Teng YH, Tan PH, Chia SJ, Zam NA, Lau WK, Cheng CW, Bay BH, Yip GW (2008) Increased expression of non-sulfated chondroitin correlates with adverse clinicopathological parameters in prostate cancer. Mod Pathol 21:893–901

    CAS  PubMed  Google Scholar 

  27. Tan PH, Jayabaskar T, Yip G, Tan Y, Hilmy M, Selvarajan S, Bay BH (2005) p53 and c-kit (CD117) protein expression as prognostic indicators in breast phyllodes tumors: a tissue microarray study. Mod Pathol 18:1527–1534

    CAS  PubMed  Google Scholar 

  28. Koo CY, Bay BH, Lui PC, Tse GM, Tan PH, Yip GW (2006) Immunohistochemical expression of heparan sulfate correlates with stromal cell proliferation in breast phyllodes tumors. Mod Pathol 19:1344–1350

    CAS  PubMed  Google Scholar 

  29. Tojkander S, Gateva G, Lappalainen P (2012) Actin stress fibers–assembly, dynamics and biological roles. J Cell Sci 125:1855–1864

    CAS  PubMed  Google Scholar 

  30. Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6:56–68

    CAS  PubMed  Google Scholar 

  31. Smilenov LB, Mikhailov A, Pelham RJ, Marcantonio EE, Gundersen GG (1999) Focal adhesion motility revealed in stationary fibroblasts. Science 286:1172–1174

    CAS  PubMed  Google Scholar 

  32. Hooper JE, Scott MP (2005) Communicating with Hedgehogs. Nat Rev Mol Cell Biol 6:306–317

    CAS  PubMed  Google Scholar 

  33. Katoh Y, Katoh M (2004) KIF27 is one of orthologs for Drosophila Costal-2. Int J Oncol 25:1875–1880

    CAS  PubMed  Google Scholar 

  34. Wang ZZ, Yang J, Jiang BH, Di JB, Gao P, Peng L, Su XQ (2018) KIF14 promotes cell proliferation via activation of Akt and is directly targeted by miR-200c in colorectal cancer. Int J Oncol 53:1939–1952

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Huang Y, Wang H, Lian Y, Wu X, Zhou L, Wang J, Deng M, Huang Y (2018) Upregulation of kinesin family member 4A enhanced cell proliferation via activation of Akt signaling and predicted a poor prognosis in hepatocellular carcinoma. Cell Death Dis 9:141

    PubMed  PubMed Central  Google Scholar 

  36. Yip GW, Ferretti P, Copp AJ (2002) Heparan sulphate proteoglycans and spinal neurulation in the mouse embryo. Development 129:2109–2119

    CAS  PubMed  Google Scholar 

  37. Goodrich LV, Johnson RL, Milenkovic L, McMahon JA, Scott MP (1996) Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 10:301–312

    CAS  PubMed  Google Scholar 

  38. Edge S, Byrd DR, Compton CC, Fritz AG, Green FL, Trotti A (2010) AJCC cancer staging manual. Springer

  39. Hoda SA, Brogi E, Koerner FC, Rosen PP (2014) Rosen’s breast pathology, 4th edn. Philadelphia, Wolters Kluwer Health

    Google Scholar 

  40. Bouchet BP, Gough RE, Ammon YC, van de Willige D, Post H, Jacquemet G, Altelaar AM, Heck AJ, Goult BT, Akhmanova A (2016) Talin-KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions. Elife 5.

  41. Weng Z, Shang Y, Yao D, Zhu J, Zhang R (2018) Structural analyses of key features in the KANK1.KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex. J Biol Chem 293:215–225

    CAS  PubMed  Google Scholar 

  42. Guo Q, Liao S, Zhu Z, Li Y, Li F, Xu C (2018) Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins. J Biol Chem 293:557–566

    CAS  PubMed  Google Scholar 

  43. Huttenlocher A, Horwitz AR (2011) Integrins in cell migration. Cold Spring Harb Perspect Biol 3:005074

    Google Scholar 

  44. Stehbens SJ, Paszek M, Pemble H, Ettinger A, Gierke S, Wittmann T (2014) CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover. Nat Cell Biol 16:561–573

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wozniak MA, Modzelewska K, Kwong L, Keely PJ (2004) Focal adhesion regulation of cell behavior. Biochim Biophys Acta 1692:103–119

    CAS  PubMed  Google Scholar 

  46. Astro V, Chiaretti S, Magistrati E, Fivaz M, de Curtis I (2014) Liprin-alpha1, ERC1 and LL5 define polarized and dynamic structures that are implicated in cell migration. J Cell Sci 127:3862–3876

    CAS  PubMed  Google Scholar 

  47. Li CC, Kuo JC, Waterman CM, Kiyama R, Moss J, Vaughan M (2011) Effects of brefeldin A-inhibited guanine nucleotide-exchange (BIG) 1 and KANK1 proteins on cell polarity and directed migration during wound healing. Proc Natl Acad Sci U S A 108:19228–19233

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kakinuma N, Roy BC, Zhu Y, Wang Y, Kiyama R (2008) Kank regulates RhoA-dependent formation of actin stress fibers and cell migration via 14-3-3 in PI3K-Akt signaling. J Cell Biol 181:537–549

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Roy BC, Kakinuma N, Kiyama R (2009) Kank attenuates actin remodeling by preventing interaction between IRSp53 and Rac1. J Cell Biol 184:253–267

    CAS  PubMed  Google Scholar 

  50. Kakinuma N, Kiyama R (2009) A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane. Biochem Biophys Res Commun 386:639–644

    CAS  PubMed  Google Scholar 

  51. Pan W, Sun K, Tang K, Xiao Q, Ma C, Yu C, Wei Z (2018) Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion. J Biol Chem 293:1944–1956

    CAS  PubMed  Google Scholar 

  52. Riobo-Del Galdo NA, Lara Montero A, Wertheimer EV (2019) Role of hedgehog signaling in breast cancer: pathogenesis and therapeutics. Cells 8.

  53. Bhateja P, Cherian M, Majumder S, Ramaswamy B (2019) The Hedgehog signaling pathway: a viable target in breast cancer? Cancers (Basel) 11.

  54. Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, Katano M (2004) Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 64:6071–6074

    CAS  PubMed  Google Scholar 

  55. Cui W, Wang LH, Wen YY, Song M, Li BL, Chen XL, Xu M, An SX, Zhao J, Lu YY, Mi XY, Wang EH (2010) Expression and regulation mechanisms of Sonic Hedgehog in breast cancer. Cancer Sci 101:927–933

    CAS  PubMed  Google Scholar 

  56. O’Toole SA, Machalek DA, Shearer RF, Millar EK, Nair R, Schofield P, McLeod D, Cooper CL, McNeil CM, McFarland A, Nguyen A, Ormandy CJ, Qiu MR, Rabinovich B, Martelotto LG, Vu D, Hannigan GE, Musgrove EA, Christ D, Sutherland RL, Watkins DN, Swarbrick A (2011) Hedgehog overexpression is associated with stromal interactions and predicts for poor outcome in breast cancer. Cancer Res 71:4002–4014

    PubMed  Google Scholar 

  57. Song L, Wang W, Liu D, Zhao Y, He J, Wang X, Dai Z, Zhang H, Li X (2016) Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer. Oncol Lett 12:1027–1033

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Shen T, Ba H, Leng Y, Yan S, Shi J, Yue S, Cheng SY (2019) Sonic Hedgehog stimulates migration of MCF-7 breast cancer cells through Rac1. J Biomed Res 33:297–307

    PubMed Central  Google Scholar 

  59. Marigo V, Tabin CJ (1996) Regulation of patched by sonic hedgehog in the developing neural tube. Proc Natl Acad Sci U S A 93:9346–9351

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Fabbro M, Henderson BR (2003) Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp Cell Res 282:59–69

    CAS  PubMed  Google Scholar 

  61. O’Brate A, Giannakakou P (2003) The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist Updat 6:313–322

    PubMed  Google Scholar 

  62. Zhang Y, Xiong Y (2001) A p53 amino-terminal nuclear export signal inhibited by DNA damage-induced phosphorylation. Science 292:1910–1915

    CAS  PubMed  Google Scholar 

  63. Fabbro M, Schuechner S, Au WW, Henderson BR (2004) BARD1 regulates BRCA1 apoptotic function by a mechanism involving nuclear retention. Exp Cell Res 298:661–673

    CAS  PubMed  Google Scholar 

  64. Cmielova J, Rezacova M (2011) p21Cip1/Waf1 protein and its function based on a subcellular localization [corrected]. J Cell Biochem 112:3502–3506

    CAS  PubMed  Google Scholar 

  65. Cazzalini O, Scovassi AI, Savio M, Stivala LA, Prosperi E (2010) Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutat Res 704:12–20

    CAS  PubMed  Google Scholar 

  66. Suzuki A, Tsutomi Y, Akahane K, Araki T, Miura M (1998) Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. Oncogene 17:931–939

    CAS  PubMed  Google Scholar 

  67. Zohny SF, Al-Malki AL, Zamzami MA, Choudhry H (2019) p21(Waf1/Cip1): its paradoxical effect in the regulation of breast cancer. Breast Cancer 26:131–137

    PubMed  Google Scholar 

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Acknowledgements

This project was supported by Grants NMRC/CIRG/1436/2015 and MOH-000152 from the National Medical Research Council, Singapore. A.J.L. was a recipient of the New Colombo Plan Scholarship from the Australian Government’s Department of Foreign Affairs and Trade. X.F.T. and K.W.L. were recipients of the NUSMed Postdoctoral Fellowships from the Yong Loo Lin School of Medicine, National University of Singapore. V.P.C.K. thanks the National University of Singapore for her NUS Research Scholarship.

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Authors and Affiliations

  1. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore

    Anton J. Lucanus, Xing Fei Tan, Kee Wah Lee, Shiyuan Guo, Victoria P. C. King, Boon Huat Bay & George W. Yip

  2. School of Anatomy, Human Biology and Physiology, University of Western Australia, Crawley, WA, 6009, Australia

    Anton J. Lucanus

  3. Division of Pathology, Singapore General Hospital, Singapore, 169856, Singapore

    Aye Aye Thike & Puay Hoon Tan

  4. Department of Statistics and Applied Probability, National University of Singapore, Singapore, 117546, Singapore

    Von Bing Yap

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  1. Anton J. Lucanus
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Correspondence to George W. Yip.

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Ethics approval 2018/2998 (2011/433/F) for the study was obtained from the SingHealth Centralised Institutional Review Board.

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Lucanus, A.J., Thike, A.A., Tan, X.F. et al. KIF21A regulates breast cancer aggressiveness and is prognostic of patient survival and tumor recurrence. Breast Cancer Res Treat 191, 63–75 (2022). https://doi.org/10.1007/s10549-021-06426-x

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