Insights into the role of RUNX1 gene in female-related cancers

Sagarika Shahriar^1†, Zarin Tasnim Rafa^1†, Maiesha Samiha Mahmood^1†, Deera Mahasin^1†, Yusha Araf^2†, Md. Asad Ullah³, MD. Hasanur Rahman⁴, Md. Akkas Ali⁵, Fatama Tous Zohora⁶, Chunfu Zheng^7,8*, Mohammad Jakir Hosen^5*

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¹ Biotechnology Program, Department of Mathematics and Natural Sciences, School of Data and Sciences, Brac University, Dhaka, Bangladesh

² Department of Biotechnology Agricultural University, Mymensingh 2202, Bangladesh

³ Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Savar, Dhaka, Bangladesh

⁴ Department of Biotechnology and Genetic Engineering, Faculty of Life Sciences, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh

⁵ Department of Genetic Engineering and Biotechnology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet, Bangladesh

⁶ Department of Biotechnology and Genetic Engineering, Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh

⁷ Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China

⁸ Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada

GPD 2022, 1(2), 147 https://doi.org/10.36922/gpd.v1i2.147

Submitted: 4 July 2022 | Accepted: 12 October 2022 | Published: 2 November 2022

© 2022 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

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Abstract

The transcription factors of runt-related transcription factor (RUNX) are important regulators of various developmental pathways, with roles in proliferation, differentiation, apoptosis, and cell lineage. One of the core subclasses of the RUNX family that codes for a number of transcription-binding proteins is the RUNX1 gene, which is located on chromosome 21q22.12. There has been extensive research on RUNX1 mutations in hematological cancers, where the most conspicuous position of several chromosomal translocations has drawn interest as a tumor suppressor. In this paper, the malignancies triggered by RUNX1 mutations, which are strongly associated with cancers of the female reproductive system, along with their diagnoses and potential treatments, are reviewed. It has been found that RUNX1 mutation plays a pervasive function in female health, including sex determination, follicular development, steroidogenesis, and the interaction of the estrogen system. In contrast, chromosomal translocations in the gene linked to RUNX1 mutation may lead to severe malignancies in females. Breast, ovarian, uterine, and cervical cancers have shown the highest frequency of genetic abnormalities in the RUNX1 gene. The second most common cause of cancer-related mortality in women is breast cancer, which is also the most common cancer. There is an opposing relationship between uterine cancer and low-grade tumors that often remain confined to the uterus. Due to the regular occurrence of promoter hypermethylation and hypomethylation changes, ovarian cancer has become the most fatal of all gynecological tumors. Finally, despite being the cancer least likely to result from RUNX1 mutation, cervical cancer can directly impair natural killer cell activity. Both hematopoietic and non-hematopoietic cancer cells can form and become tumors when the RUNX1 gene is mutated, with female malignancies being the primary target. Therefore, more research on RUNX1 gene’s pattern of expression, both in vitro and in silico, is needed to lower the incidence of female-related cancers.

Keywords

RUNX1

Chromosomal translocation

Breast cancer

Uterine cancer

Ovarian cancer

Cervical cancer

Funding

The authors received no funding from external sources.

References

[1]

National Cancer Institute, 2022, What is Cancer? Available from: https://www.cancer.gov/about-cancer/understanding/ what-is-cancer [Last accessed on 2022 Feb 05].

[2]

CDC, 2022, Basic Information about Gynecologic Cancers. Available from: https://www.cdc.gov/cancer/gynecologic/ basic_info/index.htmtext=The%20five%20main%20 types%20of,treatment%20can%20be%20most%20effective [Last acccessed on 2022 Feb 05].

[3]

Riggio AI, Blyth K, 2022, The enigmatic role of RUNX1 in female-related cancers-current knowledge and future perspectives. FEBS J, 284(15): 2345–2362. https://doi.org/10.1111/febs.14059

[4]

SEER, 2022, Cancer of the Breast (Female)-Cancer Stat Facts. Available from: https://seer.cancer.gov/statfacts/html/ breast.html [Last accessed on 2022 Sep 22].

[5]

Rahib L, Wehner MR, Matrisian LM, et al., 2021, Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open, 4(4): e214708. https://doi.org/10.1001/jamanetworkopen.2021.4708

[6]

Worldwide Cancer Research, 2019, Why haven’t We Cured Cancer yet? Our Experts have the Answers. Available from: https://www.worldwidecancerresearch.org/news-opinion/2021/march/why-havent-we-cured-cancer-yet [Last accessed on 2022 Feb 05].

[7]

Women and Cancer, 2019, Cancer Treatment Centers of America. Available from: https://www.cancercenter.com/ women-and-cancer [Last accessed on 2022 Feb 05].

[8]

Ito Y, Bae S, Chuang L, 2015, The RUNX family: Developmental regulators in cancer. Nat Rev Cancer, 15(2): 81–95. https://doi.org/10.1038/nrc3877

[9]

Ito Y, Miyazono K, 2003, RUNX transcription factors as key targets of TGF-β superfamily signaling. Curr Opin Genet Dev, 13(1): 43–47. https://doi.org/10.1016/s0959-437x(03)00007-8

[10]

Ito Y, 2008, RUNX genes in development and cancer: Regulation of viral gene expression and the discovery of RUNX family genes. Adv Cancer Res, 33–76. https://doi.org/10.1016/S0065-230X(07)99002-8

[11]

Cancer Genome Atlas Network, 2012, Comprehensive molecular portraits of human breast tumors. Nature, 490(7418): 61–70. https://doi.org/10.1038/nature11412

[12]

Bowers SR, Calero-Nieto FJ, Valeaux S, et al., 2010, RUNX1 binds as a dimeric complex to overlapping RUNX1 sites within a palindromic element in the human GM-CSF enhancer. Nucleic Acids Res, 38(18): 6124–6134. https://doi.org/10.1093/nar/gkq356

[13]

Melnikova IN, Crute BE, Wang S, et al., 1993, Sequence specificity of the core-binding factor. J Virol, 67(4): 2408–2411.

[14]

Sood R, Kamikubo Y, Liu P, 2017, Role of RUNX1 in hematological malignancies. Blood, 129: 2070–2082. https://doi.org/10.1182/blood-2016-10-687830

[15]

Huang H, Woo AJ, Waldon Z, et al., 2012, A Src family kinase- Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation. Genes Dev, 26(14): 1587–1601. https://doi.org/10.1101/gad.192054.112

[16]

Min B, Kim MK, Zhang JW, et al., 2011, Identification of RUNX3 as a component of the MST/HPO signaling pathway. J Cell Physiol, 227(2): 839–849. https://doi.org/10.1002/jcp.22887

[17]

Yagi R, Chen LF, Shigesada K, et al., 1999, A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J, 18(9): 2551–2562. https://doi.org/10.1093/emboj/18.9.2551

[18]

Mangan JK, Speck NA, 2011, RUNX1 mutations in clonal myeloid disorders: From conventional cytogenetics to next generation sequencing, a story 40 years in the making. Crit Rev Oncog, 16(1-2): 77–91. https://doi.org/10.1615/critrevoncog.v16.i1-2.80

[19]

Pratap J, Lian JB, Javed A, et al., 2006, Regulatory roles of RUNX2 in metastatic tumor and cancer cell interactions with bone. Cancer Metastasis Rev, 25(4): 589–600. https://doi.org/10.1007/s10555-006-9032-0

[20]

Stewart M, Terry A, Hu M, et al., 1997, Proviral insertions induce the expression of bone-specific isoforms of PEBP2 A (CBFA1): Evidence for a new MYC collaborating oncogene. Proc Natl Acad Sci U S A, 94(16): 8646–8651. https://doi.org/10.1073/pnas.94.16.8646

[21]

Wotton S, Stewart M, Blyth K, et al., 2002, Proviral insertion indicate a dominant oncogenic role for RUNX1/AML-1 in T-cell lymphoma. Cancer Res, 62: 7181–7185.

[22]

Vogelstein B, Kinzler KW, 2004, Cancer genes and the pathways they control. Nat Med, 10: 789–799. https://doi.org/10.1038/nm1087

[23]

National Center for Biotechnology Information. 2021, U.S. National Library of Medicine. Available from: https://www.ncbi.nlm.nih.gov/sites/entrez?db= gene&cmd=Link&LinkName=gene_pubmed&from-uid 12394 [Last accessed on 21Oct 2021].

[24]

National Center for Biotechnology Information. National Library of Medicine (US). Bethesda MD: National Center for Biotechnology Information; 1988. Available from: https://https://www.ncbi.nlm.nih. gov/gene?Db=gene&Cmd=DetailsSearch&Term=861 #bibliography [Last accessed on 2022 Oct 25].

[25]

Avramopoulos D, Cox T, Blaschak JE, et al., 1992, Linkage mapping of the AML1 gene on human chromosome 21 using a DNA polymorphism in the 3’ untranslated region. Genomics, 14(2): 506–507. https://doi.org/10.1016/s0888-7543(05)80253-8

[26]

Okuda T, Nishimura M, Nakao M, et al., 2001, RUNX1/ AML1: A central player in hematopoiesis. Int J Hematol, 74(3): 252–257. https://doi.org/10.1007/BF02982057

[27]

Chen CL, Broom DC, Liu Y, et al., 2006, RUNX1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron, 49(3): 365–377. https://doi.org/10.1016/j.neuron.2005.10.036

[28]

Asou N, 2003, The role of a runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications. Crit Rev Oncol Hematol, 45(2): 129–150. https://doi.org/10.1016/s1040-8428(02)00003-3

[29]

Wikipedia, 2022, RUNX1. Available from: https:// en.wikipedia.org/wiki/RUNX1:text=In%20humans%2C%20 the%20gene%20RUNX1,or%20promoter%202%20 (proximal) [Last accessed on 2022 Sep 22].

[30]

Bowers SR, Calero-Nieto FJ, Valeaux S, et al., 2010, Runx1 binds as a dimeric complex to overlapping Runx1 sites within a palindromic element in the human GM-CSF enhancer. Nucleic Acids Res, 38: 6124–6134. https://doi.org/10.1093/nar/gkq356

[31]

RUNX1 Mutation-My Cancer Genome. 2022. Available from: https://www.mycancergenome.org/content/ alteration/runx1-mutation [Last accessed on 2022 Sep 22].

[32]

American Association for Cancer Research (AACR), 2022, AACR Project GENIE: Powering Precision Medicine. Available from: https://www.aacr.org/professionals/ research/aacr-project-genie [Last accessed on 2022 Sep 22].

[33]

Taniuchi I, Osato M, Ito Y, 2012, Runx1: No longer just for leukemia. EMBO J, 31(21): 4098–4099. https://doi.org/10.1038/emboj.2012.282

[34]

Keita M, Bachvarova M, Morin C, et al., 2013, The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion. Cell Cycle, 12(6): 972–986.

[35]

van Bragt MP, Hu X, Xie Y, et al., 2014, RUNX1, a transcription factor mutated in breast cancer, controls the fate of ER-positive mammary luminal cells. Elife, 3: e03881. https://doi.org/10.7554/eLife.03881

[36]

Chuang LSH, Ito Y, 2010, RUNX3 is multifunctional in carcinogenesis of multiple solid tumors. Oncogene, 29(18): 2605–2615.

[37]

Agarwal N, Offermanns S, Kuner R, 2004, Conditional gene deletion in primary nociceptive neurons of trigeminal ganglia and dorsal root ganglia. Genesis, 38(3): 122–129. https://doi.org/10.1002/gene.20010

[38]

Boucher TJ, Okuse K, Bennett DL, et al., 2000, Potent analgesic effects of GDNF in neuropathic pain states. Science, 290(5489): 124–127. https://doi.org/10.1126/science.290.5489.124

[39]

Andl T, Reddy ST, Gaddapara T, et al., 2002, Wnt signals are required for the initiation of hair follicle development. Dev Cell, 2(5): 643–653. https://doi.org/10.1016/s1534-5807(02)00167-3

[40]

Osorio KM, Lilja KC, Tumbar T, 2011, RUNX1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments. J Cell Biol, 193(1): 235–250. https://doi.org/10.1083/jcb.201006068

[41]

Jagannathan-Bogdan M, Zon LI, 2013, Hematopoiesis. Development, 140: 2463–2467. https://doi.org/10.1242/dev.083147

[42]

Blyth K, Cameron ER, Neil JC, 2005, The RUNX1 genes: Gain or loss of function in cancer. Nat Rev, 5: 376–387. https://doi.org/10.1038/nrc160

[43]

Li Q, Lai Q, He C, et al., 2019, RUNX1 promotes tumour metastasis by activating the Wnt/β-catenin signalling pathway and EMT in colorectal cancer. J Exp Clin Cancer Res, 38: 334. https://doi.org/10.1186/s13046-019-1330-9

[44]

Hong D, Fritz AJ, Gordon JA, et al., 2019, RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol, 234(6): 8597–8609. https:/doi.org/10.1002/jcp.27841

[45]

Xiao WH, Liu WW, 2004, Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J Gastroenterol, 10(3): 376-380. https://doi.org/10.3748/wjg.v10.i3.376

[46]

Ito Y, 2004, Oncogenic potential of the RUNX gene family: ‘Overview’. Oncogene, 23: 4198–4208. https://doi.org/10.1038/sj.onc.1207755

[47]

Lin TC, 2022, RUNX1 and cancer. Biochim Biophys Acta Rev Cancer, 1877(3): 188715. https://doi.org/10.1016/j.bbcan.2022.188715

[48]

Na Y, Huang G, Wu J, 2020, The Role of RUNX1 in NF1- related tumors and blood disorders. Mol Cells, 43(2): 153–159. https://doi.org/10.14348/molcells.2019.0295

[49]

Mercado-Matos J, Matthew-Onabanjo AN, Shaw LM, 2017, RUNX1 and breast cancer. Oncotarget, 8(23): 36934–36935. https://doi.org/10.18632/oncotarget.17249

[50]

Fernando PG, Morolli B, Storlazzi CT, et al., 2003, Identification of RUNX1/AML1 as a classical tumor suppressor gene. Oncogene, 22(4): 538–547. https://doi.org/10.1038/sj.onc.1206141

[51]

Ferrari N, Mohammed ZM, Nixon C, et al., 2014, Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer. PLoS One, 9(6): e100759. https://doi.org/10.1371/journal.pone.0100759

[52]

De Braekeleer E, Férec C, De Braekeleer M, 2009, RUNX1 translocations in malignant hemopathies. Anticancer Res, 29(4): 1031–1037.

[53]

Walker LC, Stevens J, Campbell H, et al., 2002, A novel inherited mutation of the transcription factor RUNX1 causes thrombocytopenia and may predispose to acute myeloidleukaemia. Br J Haematol, 117: 878–881. https://doi.org/10.1046/j.1365-2141.2002.03512.x

[54]

Tuo Z, Zhang Y, Wang X, et al., 2022, RUNX1 is a promising prognostic biomarker and related to immune infiltrates of cancer-associated fibroblasts in human cancers. BMC Cancer, 22: 523. https://doi.org/10.1186/s12885-022-09632-y

[55]

Liu K, Hu H, Jiang H, et al., 2021, RUNX1 promotes MAPK signaling to increase tumor progression and metastasis via OPN in head and neck cancer. Carcinogenesis, 42(3): 414–422. https://doi.org/10.1093/carcin/bgaa116

[56]

Otálora-Otálora BA, Henríquez B, López-Kleine L, et al., 2019, RUNX family: Oncogenes or tumor suppressors (Review). Oncol Rep, 42(1): 3–19. https://doi.org/10.3892/or.2019.7149

[57]

Gaidzik VI, Teleanu V, Papaemmanuil E, et al., 2016, RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia, 30: 2160–2168. https://doi.org/10.1038/leu.2016.126

[58]

Mitsuda Y, Morita K, Kashiwazaki G, et al., 2018, RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells. Sci Rep, 8(1): 6423. https://doi.org/10.1038/s41598-018-24969-w

[59]

Ramsey J, Butnor K, Peng Z, et al., 2018, Loss of RUNX1 is associated with aggressive lung adenocarcinomas. J Cell Physiol, 233(4): 3487–3497. https://doi.org/10.1002/jcp.26201

[60]

Bogoch Y, Friedlander-Malik G, Lupu L, et al., 2017, Augmented expression of RUNX1 deregulates the global gene expression of U87 glioblastoma multiforme cells and inhibits tumor growth in mice. Tumour Biol, 39(4): 1010428317698357. https://doi.org/10.1177/1010428317698357

[61]

Liu C, Xu D, Xue B, et al., 2020, Upregulation of RUNX1 suppresses proliferation and migration through repressing VEGFA expression in hepatocellular carcinoma. Pathol Oncol Res, 26(2): 1301–1311. https://doi.org/10.1007/s12253-019-00694-1

[62]

Sun L, Wang L, Chen T, et al., 2020, LncRNA RUNX1-IT1 which is downregulated by hypoxia-driven histone deacetylase 3 represses proliferation and cancer stem-like properties in hepatocellular carcinoma cells. Cell Death Dis, 11: 95. https://doi.org/10.1038/s41419-020-2274-x

[63]

Szmajda-Krygier D, Krygier A, Jamroziak K, et al., 2022, RUNX1 and RUNX3 genes expression level in adult acute lymphoblastic leukemia-a case control study. Curr Issues Mol Biol, 44: 3455–3464. https://doi.org/10.3390/cimb44080238

[64]

Sanda T, 2017, RUNX1 in T-ALL: Tumor suppressive or oncogenic? Blood, 130(15): 1686–1688. https://doi.org/10.1182/blood-2017-08-802181

[65]

Kurokawa M, Tanaka T, Tanaka K, et al., 1996, Overexpression of the AML1 proto-oncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies. Oncogene, 12: 883–892.

[66]

Aird WC, 2011, Endothelial cell heterogeneity. Cold Spring Harb Perspect Med, 2(1): a006429. https://doi.org/10.1101/cshperspect.a006429

[67]

Sroczynska P, Lancrin C, Kouskoff V, et al., 2009, The differential activities of RUNX1 promoters define milestones during embryonic hematopoiesis. Blood, 114(26): 5279–5289. https://doi.org/10.1182/blood-2009-05-222307

[68]

Chou BK, Bai H, Gao Y, et al., 2015, The roles of RUNX1 in human hematopoiesis and megakaryopoiesis revealed by genome-targeted human iPSCs and an improved hematopoietic differentiation model. Blood, 126: 1167. https://doi.org/10.1182/blood.V126.23.1167.1167

[69]

Ichikawa M, Yoshimi A, Nakagawa M, et al., 2013, A role for RUNX1 in hematopoiesis and myeloid leukemia. Int J Hematol, 97: 726–734. https://doi.org/10.1007/s12185-013-1347-3

[70]

Hunt SP, Mantyh PW, 2001, The molecular dynamics of pain control. Nat Rev Neurosci, 2(2): 83–91. https://doi.org/10.1038/35053509

[71]

Grazzini E, Puma C, Roy MO, et al., 2004, Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats. Proc Natl Acad Sci, 101(18): 7175–7180. https://doi.org/10.1073/pnas.0307185101

[72]

Bruijn MF, Speck NA, 2004, Core-binding factors in hematopoiesis and immune function. Oncogene, 23(24): 4238–4248. https://doi.org/10.1038/sj.onc.1207763

[73]

Lei L, 2005, The zinc-finger transcription factor KLF7 is required for TrkA gene expression and the development of nociceptive sensory neurons. Genes Dev, 19(11): 1354–1364. https://doi.org/10.1101/gad.1227705

[74]

Light AR, Perl ER, 1979, Reexamination of the dorsal root projection to the spinal dorsal horn including observations on the differential termination of coarse and fine fibers. J Comp Neurol, 186(2): 117–131. http://doi.org/10.1002/ cne.901860202

[75]

Raveh E, Cohen S, Levanon D, et al., 2006, Dynamic expression of RUNX1 in skin affects hair structure. Mech Dev, 123(11): 842–850. https://doi.org/10.1016/j.mod.2006.08.002

[76]

Hoi CS, Lee SE, Lu SY, et al., 2010, RUNX1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol Cell Biol, 30(10): 2518–2536. https://doi.org/10.1128/MCB.01308-09

[77]

Hardy MH, 1992, The secret life of the hair follicle. Trends Genet, 8: 55–61. https://doi.org/10.1016/0168-9525(92)90350-d

[78]

Gat U, DasGupta R, Degenstein L, et al., 1998, De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell, 95(5): 605–614. https://doi.org/10.1016/s0092-8674(00)81631-1

[79]

Capel B, 2017, Vertebrate sex determination: Evolutionary plasticity of a fundamental switch. Nat Rev Genet, 18(11): 675–689. https://doi.org/10.1038/nrg.2017.60

[80]

Duffy JB, Gergen JP, 1991, The Drosophila segmentation gene runt acts as a position-specific numerator element necessary for the uniform expression of the sex-determining gene sex-lethal. Genes Dev, 5(12a): 2176–2187. https://doi.org/10.1101/gad.5.12a.2176

[81]

Kramer SG, Jinks TM, Schedl P, et al., 1999, Direct activation of sex-lethal transcription by the Drosophila runt protein. Development, 126(1): 191–200. https://doi.org/10.1242/dev.126.1.191

[82]

Levanon D, Brenner O, Negreanu V, et al., 2001, Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis. Mech Dev, 109(2): 413–417. https://doi.org/10.1016/s0925-4773(01)00537-8

[83]

Naillat F, Yan W, Karjalainen R, et al., 2015, Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary. Exp Cell Res, 332(2): 163–178. https://doi.org/10.1016/j.yexcr.2015.01.010

[84]

Vainio S, Heikkilä M, Kispert A, et al., 1999, Female development in mammals is regulated by Wnt-4 signalling. Nature, 397(6718): 405–409. https://doi.org/10.1038/17068

[85]

Jo M, Curry TE, 2006, Luteinizing hormone-induced runx1 regulates the expression of genes in granulosa cells of rat periovulatory follicles. Mol Endocrinol, 20(9): 2156–2172. https://doi.org/10.1210/me.2005-0512

[86]

Liu J, Park ES, Curry TE, et al., 2010, Periovulatory expression of hyaluronan and proteoglycan link protein 1 (Hapln1) in the rat ovary: Hormonal regulation and potential function. Mol Endocrinol, 24(6): 1203–1217. https://doi.org/10.1210/me.2009-0325

[87]

Jo M, Gieske MC, Payne CE, et al., 2004, Development and application of a rat ovarian gene expression database. Endocrinology, 145(11): 5384–5396. https://doi.org/10.1210/en.2004-0407

[88]

Nimz M, Spitschak M, Fürbass R, et al, 2010, The pre-ovulatory luteinizing hormone surge is followed by down-regulation of CYP19A1, HSD3B1, and CYP17A1 and chromatin condensation of the corresponding promoters in bovine follicles. Mol Reprod Dev, 77(12): 1040–1048. https://doi.org/10.1002/mrd.21257

[89]

Gao K, Wang P, Peng J, et al., 2018, Regulation and function of runt-related transcription factors (Runx1 and runx2) in goat granulosa cells. J Steroid Biochem Mol Biol, 2018;181: 98–108. https://doi.org/10.1016/j.jsbmb.2018.04.002

[90]

Hewitt SC, Winuthayanon W, Korach KS, 2016, What’s new in estrogen receptor action in the female reproductive tract. J Mol Endocrinol, 56(2): R55–R71. https://doi.org/10.1530/JME-15-0254

[91]

Hall JM, Couse JF, Korach KS, 2001, The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem, 276(40): 36869–36872. https://doi.org/10.1074/jbc.R100029200

[92]

Wall EH, Hewitt SC, Liu L, et al., 2013, Genetic control of estrogen-regulated transcriptional and cellular responses in mouse uterus. FASEB J, 27(5): 1874–1886. https://doi.org/10.1096/fj.12-213462

[93]

Stender JD, Kim K, Charn TH, et al., 2010, Genome-wide analysis of estrogen receptor α DNA binding and tethering mechanisms identifies runx1 as a novel tethering factor in receptor-mediated transcriptional activation. Mol Cell Biol, 30(16): 3943–3955. https://doi.org/10.1128/MCB.00118-10

[94]

Candelaria NR, Liu K, Lin CY, 2013, Estrogen receptor alpha: Molecular mechanisms and emerging insights. J Cell Biochem, 114(10): 2203–2208. https://doi.org/10.1002/jcb.24584

[95]

Hewitt SC, O’Brien JE, Jameson JL, et al., 2009, Selective disruption of erα DNA-binding activity alters uterine responsiveness to estradiol. Mol Endocrinol, 23(12): 2111–2116. https://doi.org/10.1210/me.2009-0356

[96]

Hovey RC, Trott JF, Vonderhaar BK, 2002, Establishing a framework for the functional mammary gland: From endocrinology to morphology. J Mammary Gland Biol Neoplasia, 7(1): 17–38. https://doi.org/10.1023/a:1015766322258

[97]

Mallepell S, Krust A, Chambon P, et al., 2006, Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A, 103(7): 2196–2201. https://doi.org/10.1073/pnas.0510974103

[98]

Janes KA, 2011, RUNX1 and its understudied role in breast cancer. Cell Cycle, 10(20): 3461–3465. https://doi.org/10.4161/cc.10.20.18029

[99]

Couse JF, Korach KS, 1999, Estrogen receptor null mice: What have we learned and where will they lead us? Endoc Rev, 20(3): 358–417. https://doi.org/10.1210/edrv.20.3.0370

[100]

Yamagata T, Maki K, et al., 2005, Runx1/aml1 in normal and abnormal hematopoiesis. Int J Hematol, 82(1): 1–8. https://doi.org/10.1532/IJH97.05075

[101]

Ramaswamy S, Ross KN, Lander ES, et al., 2003, A molecular signature of metastasis in primary solid tumors. Nat Genet, 33(1): 49–54. https://doi.org/10.1038/ng1060

[102]

Cbioportal for Cancer Genomics. Available from: https:// www.cbioportal.org/results/cancerTypesSummary?case-set-id=al l - gene - l ist-RUNX1-cancer- study - l ist - 5c8a7d55e4b046111fee2296dit [Last accessed on 2020 Oct 05].

[103]

Ellis MJ, Ding L, Shen D, et al., 2012, Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature, 486(7403): 353–360. https://doi.org/10.1038/nature11143

[104]

Banerji S, Cibulskis K, Rangel-Escareno C, et al., 2012, Sequence analysis of mutations and translocations across breast cancer subtypes. Nature, 486(7403): 405–409. https://doi.org/10.1038/nature11154

[105]

Doll A, Gonzalez M, Abal M, et al., 2009, An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis. Int J Cancer, 125(2): 257–263. https://doi.org/10.1002/ijc.24330

[106]

Planagumà J, Díaz-Fuertes M, Gil-Moreno A, et al., 2004, A differential gene expression profile reveals overexpression of runx1/aml1 in invasive endometrioid carcinoma. Cancer Res, 64(24): 8846–8853. https://doi.org/10.1158/0008-5472.CAN-04-2066

[107]

Qu J, Tanis SE, Smits JP, et al., 2018, Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape. Cell Rep, 25(12): 3490–3503.e4. https://doi.org/10.1016/j.celrep.2018.11.039

[108]

Xiao L, Peng Z, Zhu A, et al., 2020, Inhibition of RUNX1 promotes cisplatin-induced apoptosis in ovarian cancer cells. Biochem Pharmacol, 180: 114116. https://doi.org/10.1016/j.bcp.2020.114116

[109]

Han S, Zhu J, Zhang Y, 2018, Mir-144 potentially suppresses proliferation and migration of ovarian cancer cells by targeting runx1. Med Sci Monit Basic Res, 24: 40–46. https://doi.org/10.12659/msmbr.907333

[110]

Ge T, Yin M, Yang M, et al., 2014, Microrna-302b suppresses human epithelial ovarian cancer cell growth by targeting runx1. Cell Physiol Biochem, 34(6): 2209–2220. https://doi.org/10.1159/000369664

[111]

Kurita T, Mills AA, Cunha GR, 2004, Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis. Development, 131: 1639–1649. https://doi.org/10.1242/dev.01038

[112]

Marouf C, Gohler S, Filho MI, et al., 2016, Analysis of functional germline variants in APOBEC3 and driver genes on breast cancer risk in Moroccan study population. BMC Cancer, 16: 165. https://doi.org/10.1186/s12885-016-2210-8

[113]

Rody A, Karn T, Liedtke C, et al., 2011, A clinically relevant gene signature in triple negative and basal‐like breast cancer. Breast Cancer Res, 13: R97. https://doi.org/10.1186/bcr3035

[114]

Karn T, Pusztai L, Holtrich U, et al., 2011, Homogeneous datasets of triple negative breast cancers enable the identification of novel prognostic and predictive signatures. PLoS One, 6: e28403. https://doi.org/10.1371/journal.pone.0028403

[115]

Hnisz D, Abraham BJ, Lee TI, et al., 2013, Super‐enhancers in the control of cell identity and disease. Cell, 155: 934–947. https://doi.org/10.1016/j.cell.2013.09.053

[116]

Browne G, Taipaleenmaki H, Bishop NM, et al., 2015, RUNX1 is associated with breast cancer progression in MMTV‐PyMT transgenic mice and its depletion in vitro inhibits migration and invasion. J Cell Physiol, 230: 2522–2532. https://doi.org/10.1002/jcp.24989

[117]

Kadota M, Yang HH, Gomez B, et al., 2010, Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. PLoS One, 5: e9201. https://doi.org/10.1371/journal.pone.0009201

[118]

Bokhman JV, 1983, Two pathogenetic types of endometrial carcinoma. Gynecol Oncol, 15: 10–17. https://doi.org/10.1016/0090-8258(83)90111-7

[119]

Planaguma J, Abal M, Gil‐Moreno A, et al., 2005, Up‐regulation of ERM/ETV5 correlates with the degree of myometrial infiltration in endometrioid endometrial carcinoma. J Pathol, 207: 422–429. https://doi.org/10.1002/path.1853.

[120]

Planaguma J, Liljestrom M, Alameda F, et al., 2011, Matrix metalloproteinase‐2 and matrix metalloproteinase‐9 codistribute with transcription factors RUNX1/AML1 and ETV5/ERM at the invasive front of endometrial and ovarian carcinoma. Hum Pathol, 42: 57–67. https://doi.org/10.1016/j.humpath.2010.01.025

[121]

Atienza JM, Roth RB, Rosette C, et al., 2005, Suppression of RAD21 gene expression decreases cell growth and enhances cytotoxicity of etoposide and bleomycin in human breast cancer cells. Mol Cancer Ther 4: 361–368. https://doi.org/10.1158/1535-7163.MCT-04-0241

[122]

Rhodes DR, Yu J, Shanker K, et al., 2004, Large‐scale meta‐analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci U S A 101: 9309–9314. https://doi.org/10.1073/pnas.0401994101

[123]

Alonso‐Alconada L, Muinelo‐Romay L, Madissoo K, et al., 2014, Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer. Mol Cancer, 13: 223. https://doi.org/10.1186/1476-4598-13-223

[124]

Ferlay J, Soerjomataram I, Dikshit R, et al., 2015, Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 136(5): E359–E386. https://doi.org/10.1002/ijc.29210

[125]

Jemal A, Bray F, Center MM, et al., 2011, Global cancer statistics. CA Cancer J Clin. 61(2): 69–90. https://doi.org/10.3322/caac.20107

[126]

WCRF International. 2021, Ovarian Cancer Statistics. World Cancer Research Fund International. Available from: https:// www.wcrf.org/dietandcancer/ovarian-cancer-statistics [Last accessed on 2021 Oct 25].

[127]

Mills K, Fuh K, 2017, Recent advances in understanding, diagnosing, and treating ovarian cancer. F1000Research, 6: 84. https://doi.org/10.12688/f1000research.9977.1

[128]

Vogelstein B, Papadopoulos N, Velculescu VE, et al., 2013, Cancer genome landscapes. Science, 339(6127): 1546–1558. https://doi.org/10.1126/science.1235122

[129]

Yu H, Pardoll D, Jove R, et al., 2009, STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer, 9(11): 798–809. https://doi.org/10.1038/nrc2734

[130]

Monge M, Colas E, Doll A, et al., 2007, ERM/ETV5 up-regulation plays a role during myometrial infiltration through matrix metalloproteinase-2 activation in endometrial cancer. Cancer Res, 67(14): 6753–6759. https://doi.org/10.1158/0008-5472.CAN-06-4487

[131]

Aylward J, 2021, Global Burden of Cervical Cancer-together for Health TogetHER for Health. Available from: https:// togetherforhealth.org/global-burden-cervical-cancer [Last accesed on 2021 Oct 25].

[132]

SEER, 2022, Cancer of the Cervix Uteri Cancer Stat Facts. Available from: https://seer.cancer.gov/statfacts/html/ cervix.html [Last accessed on 2022 Sep 22].

[133]

Laronda MM, Unno K, Ishi K, et al., 2013, Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1- mediated cell fate decision in the Müllerian duct epithelium. Dev Biol, 381: 5–16. https://doi.org/10.1016/j.ydbio.2013.06.024

[134]

Terakawa J, Rocchi A, Serna VA, et al., 2016, FGFR2IIIb- MAPK activity is required for epithelial cell fate decision in the lower Müllerian duct. Mol Endocrinol, 30: 783–795. https://doi.org/10.1210/me.2016-1027

[135]

Robboy SJ, Young RH, Welch WR, et al., 1984, Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring. Cancer, 54: 869–875. https://doi.org/10.1002/1097-0142(19840901)54:5<869:aid-cncr2820540519>3.0.co;2-i

[136]

Cerami E, Gao J, Dogrusoz U, et al., 2012, The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov, 2(5): 401–404. https://doi.org/10.1158/2159-8290.CD-12-0095

[137]

Gao J, Aksoy BA, Dogrusoz U, et al., 2013, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal, 6(269): l1. https://doi.org/10.1126/scisignal.2004088

[138]

Min D, Lv WB, Wang X, et.al., 2013, Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the suscepti-bility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer, 109: 723–730. https://doi.org/10.1038/bjc.2013.337

[139]

Zhang Q, Di W, Dong Y, et al., 2015, High serum miR-183 level is associated with poor responsiveness of renal cancer to natural killer cells. Tumor Biol, 36: 9245–9249. https://doi.org/10.1007/s13277-015-3604-y

[140]

Kang HW, Wang F, Wei Q, et al., 2012, miR-20a promotes migration and invasion by regulating TNKS2 in human cervical cancer cells. FEBS Lett, 586(6): 897–904. https://doi.org/10.1016/j.febslet.2012.02.020

[141]

Zhu SY, Wu QY, Zhang CX, et al., 2018, miR-20a inhibits the killing effect of natural killer cells to cervical cancer cells by downregulating RUNX1. Biochem Biophys Res Commun, 505(1): 309–316. https://doi.org/10.1016/j.bbrc.2018.09.102

[142]

Ohno SI, Sato T, Kohu K, et al., 2008, Runx proteins are involved in regulation of CD122, Ly49 family and IFN-γ expression during NK cell differentiation. Int Immunol, 20(1): 71–79. https://doi.org/10.1093/intimm/dxm120

[143]

Su JH, Wu A, Scotney E, et al., 2010, Immunotherapy for cervical cancer. BioDrugs, 24: 109–129. https://doi.org/10.2165/11532810-000000000-00000

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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