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RUNX1 as a Novel Molecular Target for Breast Cancer

  • Nur Syamimi Ariffin
    Correspondence
    Address for correspondence: Nur Syamimi Ariffin, Department of Pharmacology and Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA, UiTM Selangor Branch, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia
    Affiliations
    Department of Pharmacology and Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA, Selangor, Malaysia
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Published:April 25, 2022DOI:https://doi.org/10.1016/j.clbc.2022.04.006

      Abstract

      RUNX1 has long known for its role in hematopoiesis until recently it is implicated in human breast cancer pathogenesis. This has drawn attention in research as elevated expression of RUNX1 has been observed in invasive breast cancer, and mutations of the RUNX1 gene and its binding partner CBFβ have been identified in luminal breast cancer patients, many of which have attributed to the development and progression of the disease. Increasing number of evidence also shows the involvement of RUNX1 in breast cancer migration and invasion that may lead to breast cancer metastasis. However, more studies need to be conducted to better understand its roles in these particular subtypes in breast cancer. This is important as evidence so far indicates that there are discrepancies with regards to the roles of RUNX1 in ER-positive and ER-negative breast cancer, both of which have posted a great challenge to recognize whether its deregulation is protecting or promoting breast cancer. This warrants further analysis to glean more information especially considering the perturbation of RUNX1 is mainly reported in ER-positive breast cancer. In this review, the roles of RUNX1 in breast cancer are discussed in a context dependent manner based on its involvement in the development and progression of the disease. The association of RUNX1 with other types of cancer is also included to emphasize a wider and possibly a different angle of involvement of RUNX1 in cancer.

      Keywords

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      References

      1. World Health Organization. Retrieved from https://www.who.int. Accessed December 15, 2021.

        • Mercado-Matos J
        • Matthew-Onabanjo AN
        • Shaw LM.
        RUNX1 and breast cancer.
        Oncotarget. 2017; 8: 36934-36935https://doi.org/10.18632/oncotarget.17249
        • Ito Y.
        RUNX genes in development and cancer: regulation of viral gene expression and the discovery of RUNX family genes.
        Adv Cancer Res. 2008; : 33-76https://doi.org/10.1016/S0065-230X(07)99002-8
        • Okuda T
        • Deursen JV
        • Hiebert SW
        • Grosveld G
        • Downing JR.
        AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver haematopoiesis.
        Cell. 1996; 84: 321-330https://doi.org/10.1016/S0092-8674(00)80986-1
        • Miyoshi H
        • Shimizu K
        • Kozu T
        • Maseki N
        • Kaneko Y
        • Ohki M.
        t(8;21) breakpoints on chromosome 21 in acute myeloid leukaemia are clustered within a limited region of a single gene, AML1.
        PNAS. 1991; 88: 10431-10434https://doi.org/10.1073/pnas.88.23.10431
        • Hatlen MA
        • Wang L
        • Nimer SD.
        AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches.
        Front Med. 2012; 6: 248-262https://doi.org/10.1007/s11684-012-0206-6
        • Okuda T
        • Cai Z
        • Yang S
        • et al.
        Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors.
        Blood. 1998; 91 (http://www.ncbi.nlm.nih.gov/pubmed/9558367): 3134-3143
        • Fischer M
        • Schwieger M
        • Horn S
        • et al.
        Defining the oncogenic function of the TEL//AML1 (ETV6//RUNX1) fusion protein in a mouse model.
        Oncogene. 2005; 24: 7579-7591https://doi.org/10.1038/sj.onc.1208931
        • Mitani K
        • Ogawa S
        • Tanaka T
        • et al.
        Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia.
        EMBO J. 1994; 13: 504-510
        • Castilla LH
        • Wijmenga C
        • Wang Q
        • et al.
        Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukaemia gene CBFB-MYH11.
        Cell. 1996; 87: 687-696https://doi.org/10.1016/S0092-8674(00)81388-4
        • Hong D
        • Fritz AJ
        • Gordon JA
        • et al.
        RUNX1-dependent mechanisms in biological control and dysregulation in cancer.
        J Cell Physiol. 2019; 234: 8597-8609https://doi.org/10.1002/jcp.27841
        • Taniuchi I
        • Osato M
        • Ito Y.
        RUNX1: no longer just for leukaemia.
        EMBO J. 2012; 31: 4098-4099https://doi.org/10.1038/emboj.2012.282
        • Banerji S
        • Cibulskis K
        • Rangel-Escareno C
        • et al.
        Sequence analysis of mutations and translocations across breast cancer subtypes.
        Nature. 2012; 486: 405-409https://doi.org/10.1038/nature11154
        • Ellis MJ
        • Ding L
        • Shen D
        • et al.
        Whole-genome analysis informs breast cancer response to aromatase inhibition.
        Nature. 2012; 486: 353-360https://doi.org/10.1038/nature11143
        • Kadota M
        • Yang HH
        • Gomez B
        • et al.
        Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines.
        PLoS One. 2010; 5: e9201https://doi.org/10.1371/journal.pone.0009201
      2. Breastcancer.org. Retrieved from https://www.breastcancer.org Accessed November 10, 2021.

        • Dall GV
        • Britt KL.
        Estrogen effects on the mammary gland in early and late life and breast cancer risk.
        Front Oncol. 2017; 7: 1-10https://doi.org/10.3389/fonc.2017.00110
        • Tulinius H
        • Sigvaldason H
        • Olafsdottir G.
        Left and right sided breast cancer.
        Pathol Res Pract. 1990; 186: 92-94https://doi.org/10.1016/S0344-0338(11)81015-0
        • Perkins CI
        • Hotes J
        • Kohler BA
        • et al.
        Association between breast cancer laterality and tumor location, United States, 1994–1998.
        Cancer Causes Control. 2004; 15: 637-645https://doi.org/10.1023/B:CACO.0000036171.44162.5f
        • Zeeneldin AA
        • Ramadan M
        • Elmashad N
        • Fakhr I
        • Diaa A
        • Mosaad E.
        Breast cancer laterality among Egyptian patients and its association with treatments and survival.
        J Egypt Natl Canc Inst. 2013; 25: 199-207https://doi.org/10.1016/j.jnci.2013.09.003
        • Fatima N
        • Zaman MU
        • Maqbool A
        • Khan SH
        • Riaz N.
        Lower incidence but more aggressive behavior of right sided breast cancer in Pakistani women: does right deserve more respect? Asian Pacific.
        J Cancer Prev. 2013; 14: 43-45https://doi.org/10.7314/APJCP.2013.14.1.43
        • Bill R
        • Christofori G.
        The relevance of EMT in breast cancer metastasis: correlation or causality?.
        FEBS Lett. 2015; 589: 1577-1587https://doi.org/10.1016/j.febslet.2015.05.002
        • Hong D
        • Messier TL
        • Tye CE
        • et al.
        RUNX1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition.
        Oncotarget. 2017; 8: 17610-17627https://doi.org/10.18632/oncotarget.15381
        • Zhao J.
        Cancer stem cells and chemoresistance: the smartest survives the raid.
        Pharmacol Ther. 2016; 160: 145-158https://doi.org/10.1016/j.pharmthera.2016.02.008
        • Grigore AD
        • Jolly MK
        • Jia D
        • Farach-Carson MC
        • Levine H.
        Tumour budding: the name is EMT. Partial EMT.
        J Clin Med. 2016; 5: 51https://doi.org/10.3390/jcm5050051
        • Hong D
        • Fritz AJ
        • Finstad KH
        • et al.
        Suppression of breast cancer stem cells and tumor growth by the RUNX1 transcription factor.
        Mol Cancer Res. 2018; 16: 1952-1964https://doi.org/10.1158/1541-7786.MCR-18-0135
        • Fritz AJ
        • Hong D
        • Boyd J
        • et al.
        RUNX1 and RUNX2 transcription factors function in opposing roles to regulate breast cancer stem cells.
        J Cell Physiol. 2020; 235: 7261-7272https://doi.org/10.1002/jcp.29625
        • Ran R
        • Harrison H
        • Ariffin NS
        • et al.
        A role for CBFβ in maintaining the metastatic phenotype of breast cancer cells.
        Oncogene. 2020; 39: 2624-2637https://doi.org/10.1038/s41388-020-1170-2
        • Matsuo J
        • Mon NN
        • Douchi D
        • et al.
        A RUNX1-enhancer element eR1 identified lineage restricted mammary luminal stem cells.
        Stem Cells. 2022; 40: 112-122https://doi.org/10.1093/stmcls/sxab009
        • Matsuo J
        • Kimura S
        • Yamamura A
        • et al.
        Identification of stem cells in the epithelium of the stomach corpus and antrum of mice.
        Gastroenterology. 2017; 152: 218-231https://doi.org/10.1053/j.gastro.2016.09.018
        • Browne G
        • Taipaleenmaki H
        • Bishop NM
        • et al.
        RUNX1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion.
        J Cell Physiol. 2015; 230: 2522-2532https://doi.org/10.1002/jcp.24989
        • Browne G
        • Dragon JA
        • Hong D
        • et al.
        MicroRNA-378-mediated suppression of RUNX1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells.
        Tumour Biol. 2016; 37: 8825-8839https://doi.org/10.1007/s13277-015-4710-6
        • Ran R.
        RUNX Transcription Factors Drive Epithelial to Mesenchymal Transition in Metastatic Breast Cancer Cells.
        The University of Manchester, United Kingdom2017
        • Lamouille S
        • Xu J
        • Derynck R.
        Molecular mechanisms of epithelial-mesenchymal transition.
        Nat Rev Mol Cell Biol. 2014; 15: 178-196https://doi.org/10.1038/nrm3758
        • Tahara RK
        • Brewer TM
        • Theriault RL
        • Ueno NT.
        Bone metastasis of breast cancer.
        in: Ahmad A. Breast Cancer Metastasis and Drug Resistance. Advances in Experimental Medicine and Biology. Springer, Cham2019: 1152https://doi.org/10.1007/978-3-030-20301-6_7
        • Zhang Y
        • Ma B
        • Fan Q.
        Mechanisms of breast cancer bone metastasis.
        Cancer Lett. 2010; 292: 1-7https://doi.org/10.1016/j.canlet.2009.11.003
        • Rashid NS
        • Grible JM
        • Clevenger CV
        • Harrell JC.
        Breast cancer liver metastasis: current and future treatment approaches.
        Clin Exp Metastasis. 2021; 38: 263-277https://doi.org/10.1007/s10585-021-10080-4
        • Pratap J
        • Lian JB
        • Stein GS.
        Metastatic bone disease: role of transcription factors and future targets.
        Bone. 2011; 48: 30-36https://doi.org/10.1016/j.bone.2010.05.035
        • Lu C
        • Yang Z
        • Yu D
        • Lin J
        • Cai W.
        RUNX1 regulates TGF-β induced migration and EMT in colorectal cancer.
        Pathol Res Pract. 2020; 216153142https://doi.org/10.1016/j.prp.2020.153142
        • Li Q
        • Lai Q
        • He C
        • et al.
        RUNX1 promotes tumour metastasis by activating the Wnt/β-catenin signalling pathway and EMT in colorectal cancer.
        J Exp Clin Cancer Res. 2019; 38: 334https://doi.org/10.1186/s13046-019-1330-9
        • Chimge NO
        • Ahmed-Alnassar S
        • Frenkel B.
        Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive breast cancer.
        Cell Cycle. 2017; 16: 312-318https://doi.org/10.1080/15384101.2016.1237325
        • Fu Y
        • Sun S
        • Man X
        • Kong C.
        Increased expression of RUNX1 in clear cell renal cell carcinoma predicts poor prognosis.
        Peer J. 2019; 7: e7854https://doi.org/10.7717/peerj.7854
        • Sweeney K
        • Cameron ER
        • Blyth K.
        Complex interplay between the RUNX transcription factors and Wnt/β-catenin pathway in cancer: a tango in the night.
        Mol Cells. 2020; 43: 188-197https://doi.org/10.14348/molcells.2019.0310
        • Rooney N
        • Riggio AI
        • Mendoza-Villanueva D
        • Shore P
        • Cameron ER
        • Blyth K.
        RUNX genes in breast cancer and the mammary lineage.
        in: Groner Y Ito Y Liu P Neil J Speck N van Wijnen A. RUNX Proteins in Development and Cancer. Advances in Experimental Medicine and Biology. Springer, Singapore2017: 962https://doi.org/10.1007/978-981-10-3233-2_22
        • Ariffin NS.
        The Mesenchymal-Like Phenotype of Metastatic Breast Cancer Is Maintained by the Transcription Factor RUNX1.
        The University of Manchester, United Kingdom2017
        • Chalmers ZR
        • Connelly CF
        • Fabrizio D
        • et al.
        Analysis of 100,000 human cancer genomes reveals the landscape of tumour mutational burden.
        Genome Med. 2017; 9: 34https://doi.org/10.1186/s13073-017-0424-2
        • Gupta S
        • Artomov M
        • Goggins W
        • Daly M
        • Tsao H.
        Gender disparity and mutation burden in metastatic melanoma.
        J Natl Cancer Inst. 2015; 107: 1-4https://doi.org/10.1093/jnci/djv221
        • Rizvi NA
        • Hellmann MD
        • Snyder A
        • et al.
        Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
        Science. 2015; : 124-128https://doi.org/10.1126/science.aaa1348
        • Klebanov N
        • Artomov M
        • Goggins WB
        • et al.
        Burden of unique and low prevalence somatic mutations correlates with cancer survival.
        Sci Rep. 2019; 9: 4848https://doi.org/10.1038/s41598-019-41015-5
        • Babiker HM
        • McBride A
        • Newton M
        • et al.
        Cardiotoxic effects of chemotherapy: a review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system.
        Crit Rev Oncol Hematol. 2018; 126: 186-200https://doi.org/10.1016/j.critrevonc.2018.03.014
        • Gebauer J
        • Higham C
        • Langer T
        • Denzer C
        • Brabant G.
        Long-term endocrine and metabolic consequences of cancer treatment: a systematic review.
        Endocr Rev. 2019; 40: 711-767https://doi.org/10.1210/er.2018-00092
        • Staff NP
        • Grisold A
        • Grisold W
        • Windebank AJ.
        Chemotherapy-induced peripheral neuropathy: a current review.
        Ann Neurol. 2017; 81: 772-781https://doi.org/10.1002/ana.24951
        • Rada M
        • Kapelanski-Lamoureux A
        • Petrillo S.
        • et al.
        Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases.
        Commun Biol. 2021; 4: 950https://doi.org/10.1038/s42003-021-02481-8
        • Itatani Y
        • Kawada K
        • Sakai Y.
        Transforming growth factor-β signalling pathway in colorectal cancer and its tumour microenvironment.
        Int J Mol Sci. 2019; 20: 5822https://doi.org/10.3390/ijms20235822
        • Hu HH
        • Chen DQ
        • Wang YN
        • et al.
        New insights into TGF-β/Smad signalling in tissue fibrosis.
        Chem Biol Interact. 2018; 292: 76-83https://doi.org/10.1016/j.cbi.2018.07.008
        • Voon DCC
        • Thiery JP.
        The emerging roles of RUNX transcription factors in epithelial-mesenchymal transition.
        in: Groner Y. Ito Y. Liu P. Neil J. Speck N. van Wijnen A. RUNX Proteins in Development and Cancer. Advances in Experimental Medicine and Biology. Springer, Singapore2017: 962https://doi.org/10.1007/978-981-10-3233-2_28
        • Qiu WX
        • Ma XL
        • Lin X
        • et al.
        Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway.
        J Cell Mol Med. 2020; 24: 317-327https://doi.org/10.1111/jcmm.14729
        • Xiao Z
        • Tian Y
        • Jia Y
        • et al.
        RUNX3 inhibits the invasion and migration of oesophageal squamous cell carcinoma by reversing the epithelialmesenchymal transition through TGFβ/Smad signalling.
        Oncol Rep. 2020; 43: 1289-1299https://doi.org/10.3892/or.2020.7508
        • Soleimani A
        • Pashirzad M
        • Avan A
        • Ferns GA
        • Khazaei M
        • Hassanian SM.
        Role of the transforming growth factor-β signaling pathway in the pathogenesis of colorectal cancer.
        J Cell Biochem. 2019; 120: 8899-8907https://doi.org/10.1002/jcb.28331
        • Zhou T
        • Luo M
        • Cai W
        • et al.
        Runt-related transcription factor 1 (RUNX1) promotes TGF-β-induced renal tubular epithelial-to-mesenchymal transition (EMT) and renal fibrosis through the PI3K subunit p110δ.
        EBioMedicine. 2018; 31: 217-225https://doi.org/10.1016/j.ebiom.2018.04.023
        • Zhao K
        • Cui X
        • Wang Q
        • et al.
        RUNX1 contributes to the mesenchymal subtype of glioblastoma in a TGFβ pathway-dependent manner.
        Cell Death Dis. 2019; 10: 877https://doi.org/10.1038/s41419-019-2108-x
        • Barutcu AR
        • Hong D
        • Lajoie BR
        • et al.
        RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.
        Biochim Biophys Acta. 2016; 1859: 1389-1397https://doi.org/10.1016/j.bbagrm.2016.08.003
        • Ito Y
        • Bae SC
        • Chuang LS.
        The RUNX family: developmental regulators in cancer.
        Nat Rev Cancer. 2015; 15: 81-95https://doi.org/10.1038/nrc3877
        • van Bragt MPA
        • Hu X
        • Xie Y
        • Li Z.
        RUNX1, a transcription factor mutated in breast cancer, controls the fate of ER-positive mammary luminal cells.
        eLife. 2015; 3: e03881https://doi.org/10.7554/eLife.03881.001
        • Malik N
        • Yan H
        • Moshkovich N
        • et al.
        The transcription factor CBFβ suppresses breast cancer through orchestrating translation and transcription.
        Nat Commun. 2019; 10: 2071https://doi.org/10.1038/s41467-019-10102-6
        • Chimge NO
        • Little GH
        • Baniwal SK
        • et al.
        RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer.
        Nat Commun. 2016; 7: 10751-10773https://doi.org/10.1038/ncomms10751
        • Ferrari N
        • Mohammed ZMA
        • Nixon C
        • et al.
        Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer.
        PLoS One. 2014; 9e100759https://doi.org/10.1371/journal.pone.0100759
        • Recouvreux MS
        • Grasso EN
        • Echeverria PC
        • et al.
        RUNX1 and FOXP3 interplay regulates expression of breast cancer related genes.
        Oncotarget. 2016; 7: 6552-6565https://doi.org/10.18632/oncotarget.6771
      3. WorldLifeExpectancy. Retrieved from https://www.worldlifeexpectancy.com Accessed December 25, 2021.