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Comprehensive analysis of the homeobox family genes in breast cancer demonstrates their similar roles in cancer and development

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Abstract

Background

The homeobox (HOX) family consists of 39 genes whose expressions are tightly controlled and coordinated within the family, during development. We performed a comprehensive analysis of this gene family in cancer settings.

Methods

Gene correlation analysis was performed using breast cancer data available in The Cancer Genome Atlas (TCGA) and data from the patients admitted to our hospital. We also analyzed the data of normal breast tissue (GSE20437). We next collected gene expression and prognosis data of breast cancer patients (GSE11121, GSE7390, GSE3494, and GSE2990) and performed unsupervised hierarchal clustering by the HOX gene expression pattern and compared prognosis. We additionally performed this analysis to leukemia (available in TCGA) and sarcoma (GSE20196) data.

Results

Gene correlation analysis showed that the proximal HOX genes exhibit strong interactions and are expressed together in breast cancer, similar to the expression observed during development. However, in normal breast tissue, less interactions were observed. Breast cancer microarray meta-data classified by the HOX gene expression pattern predicted the prognosis of luminal B breast cancer patients (p = 0.016). Leukemia (p = 0.00016) and sarcoma (p = 0.018) presented similar results. The Wnt signaling pathway, one of the major upstream signals of HOX genes in development, was activated in the poor prognostic group. Interestingly, poor prognostic cancer presented stronger correlation in the gene family compared to favorable prognostic cancer.

Conclusion

Comprehensive analysis of the HOX family demonstrated their similar roles in cancer and development, and indicated that the strong interaction of HOX genes might be specific to malignancies, especially in the case of poor prognostic cancer.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Shah N, Sukumar S (2010) The Hox genes and their roles in oncogenesis. Nat Rev Cancer 10:361–371. https://doi.org/10.1038/nrc2826

    Article  CAS  PubMed  Google Scholar 

  2. Wellik DM (2009) Hox genes and vertebrate axial pattern. Current topics in developmental biology. Elsevier, Amsterdam, pp 257–278

    Google Scholar 

  3. Deschamps J, Duboule D (2017) Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock. Genes Dev 31:1406–1416. https://doi.org/10.1101/gad.303123.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rux DR, Wellik DM (2017) Hox genes in the adult skeleton: novel functions beyond embryonic development. Dev Dyn 246:310–317. https://doi.org/10.1002/dvdy.24482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. de Bessa Garcia SA, Araújo M, Pereira T et al (2020) HOX genes function in breast cancer development. Biochim Biophys Acta - Rev Cancer. https://doi.org/10.1016/j.bbcan.2020.188358

    Article  PubMed  Google Scholar 

  6. Huang D, Guo G, Yuan P et al (2017) The role of Cdx2 as a lineage specific transcriptional repressor for pluripotent network during the first developmental cell lineage segregation. Sci Rep 7:17156. https://doi.org/10.1038/s41598-017-16009-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rawat VPS, Thoene S, Naidu VM et al (2008) Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia. Blood. https://doi.org/10.1182/blood-2007-04

    Article  PubMed  Google Scholar 

  8. Neijts R, Amin S, van Rooijen C, Deschamps J (2017) Cdx is crucial for the timing mechanism driving colinear Hox activation and defines a trunk segment in the Hox cluster topology. Dev Biol 422:146–154. https://doi.org/10.1016/j.ydbio.2016.12.024

    Article  CAS  PubMed  Google Scholar 

  9. Young T, Elizabeth Rowland J, van de Ven C et al (2009) Cdx and Hox genes differentially regulate posterior axial growth in mammalian embryos. Dev Cell 17:516–526. https://doi.org/10.1016/j.devcel.2009.08.010

    Article  CAS  PubMed  Google Scholar 

  10. Denans N, Iimura T, Pourquié O (2015) Hox genes control vertebrate body elongation by collinear Wnt repression. Elife. https://doi.org/10.7554/eLife.04379

    Article  PubMed  PubMed Central  Google Scholar 

  11. Soshnikova N, Duboule D (2009) Epigenetic temporal control of mouse Hox genes in vivo. Science 324:1320–1323. https://doi.org/10.1126/science.1171468

    Article  CAS  PubMed  Google Scholar 

  12. Jambhekar A, Dhall A, Shi Y (2019) Roles and regulation of histone methylation in animal development. Nat Rev Mol Cell Biol 20:625–641. https://doi.org/10.1038/s41580-019-0151-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Noordermeer D, Leleu M, Splinter E et al (2011) The dynamic architecture of Hox gene clusters. Science 334:222–225. https://doi.org/10.1126/science.1207194

    Article  CAS  PubMed  Google Scholar 

  14. De Kumar B, Krumlauf R (2016) HOX s and lincRNAs: two sides of the same coin. Sci Adv 2:e1501402. https://doi.org/10.1126/sciadv.1501402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Botti G, De Chiara A, Di Bonito M et al (2019) Noncoding RNAs within the HOX gene network in tumor pathogenesis and progression. J Cell Physiol 234:395–413. https://doi.org/10.1002/jcp.27036

    Article  CAS  Google Scholar 

  16. Bhatlekar S, Fields JZ, Boman BM (2014) HOX genes and their role in the development of human cancers. J Mol Med 92:811–823. https://doi.org/10.1007/s00109-014-1181-y

    Article  CAS  PubMed  Google Scholar 

  17. Jin K, Sukumar S (2016) HOX genes: major actors in resistance to selective endocrine response modifiers. Biochim Biophys Acta - Rev Cancer 1865:105–110. https://doi.org/10.1016/j.bbcan.2016.01.003

    Article  CAS  Google Scholar 

  18. Wang J, Chen J, Wang Y (2015) Prognostic role of HOTAIR in four estrogen- dependent malignant tumors: a meta-analysis. Onco Targets Ther. https://doi.org/10.2147/OTT.S84687

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shah N, Jin K, Cruz LA et al (2013) HOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERα and inducing IL-6 expression. Cancer Res 73:5449–5458. https://doi.org/10.1158/0008-5472.CAN-13-1178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhong Z, Shan M, Wang J et al (2015) HOXD13 methylation status is a prognostic indicator in breast cancer. Int J Clin Exp Pathol 8:10716–10724

    PubMed  PubMed Central  Google Scholar 

  21. Hayashida T, Takahashi F, Chiba N et al (2010) HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci USA 107:1100–1105. https://doi.org/10.1073/pnas.0912710107

    Article  CAS  PubMed  Google Scholar 

  22. Zhussupova A, Hayashida T, Takahashi M et al (2014) An E2F1-HOXB9 transcriptional circuit is associated with breast cancer progression. PLoS ONE 9:1–11. https://doi.org/10.1371/journal.pone.0105285

    Article  CAS  Google Scholar 

  23. Carrio M, Arderiu G, Myers C, Boudreau NJ (2005) Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model. Cancer Res 65:7177–7185. https://doi.org/10.1158/0008-5472.CAN-04-1717

    Article  CAS  PubMed  Google Scholar 

  24. Nakashoji A, Hayashida T, Kawai Y et al (2020) Identification of a modified HOXB9 mRNA in breast cancer. J Oncol. https://doi.org/10.1155/2020/6065736

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nolte C, Jinks T, Wang X et al (2013) Shadow enhancers flanking the HoxB cluster direct dynamic Hox expression in early heart and endoderm development. Dev Biol 383:158–173. https://doi.org/10.1016/J.YDBIO.2013.09.016

    Article  CAS  PubMed  Google Scholar 

  26. Neijts R, Deschamps J (2017) At the base of colinear Hox gene expression: cis -features and trans -factors orchestrating the initial phase of Hox cluster activation. Dev Biol 428:293–299. https://doi.org/10.1016/j.ydbio.2017.02.009

    Article  CAS  PubMed  Google Scholar 

  27. Deschamps J, van Nes J (2005) Developmental regulation of the Hox genes during axial morphogenesis in the mouse. Development 132:2931–2942. https://doi.org/10.1242/DEV.01897

    Article  CAS  PubMed  Google Scholar 

  28. Ordóñez-Morán P, Dafflon C, Imajo M et al (2015) HOXA5 counteracts stem cell traits by inhibiting Wnt signaling in colorectal cancer. Cancer Cell 28:815–829. https://doi.org/10.1016/j.ccell.2015.11.001

    Article  CAS  PubMed  Google Scholar 

  29. Nguyen DX, Chiang AC, Zhang XHF et al (2009) WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138:51–62. https://doi.org/10.1016/j.cell.2009.04.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Paço A, de Bessa Garcia SA, Freitas R (2020) Methylation in HOX clusters and its applications in cancer therapy. Cells 9:1–20. https://doi.org/10.3390/cells9071613

    Article  CAS  Google Scholar 

  31. Marcinkiewicz KM, Gudas LJ (2014) Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma. J Cell Physiol 229:1405–1416. https://doi.org/10.1002/jcp.24577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Collins CT, Hess JL (2016) Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets. Oncogene 35:1090–1098. https://doi.org/10.1038/onc.2015.174

    Article  CAS  PubMed  Google Scholar 

  33. Manzo G (2019) Similarities between embryo development and cancer process suggest new strategies for research and therapy of tumors: a new point of view. Front Cell Dev Biol 7:20. https://doi.org/10.3389/fcell.2019.00020

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cofre J, Abdelhay E (2017) Cancer is to embryology as mutation is to genetics: hypothesis of the cancer as embryological phenomenon. Sci World J 2017:3578090. https://doi.org/10.1155/2017/3578090

    Article  CAS  Google Scholar 

  35. Ben-David U, Benvenisty N (2011) The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 11:268–277. https://doi.org/10.1038/nrc3034

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors greatly thank Mr. Kazuya Takakuwa for help in bioinformatics analysis. They also thank Mr. Kazuhiro Miyao for scientific advice.

Funding

This work was supported by Japan Society for the Promotion of Science (Grant Number 19K23897).

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Authors and Affiliations

  1. Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 160-0016, Japan

    Ayako Nakashoji, Tetsu Hayashida, Shigeo Yamaguchi, Yuko Kawai, Masayuki Kikuchi, Takamichi Yokoe, Aiko Nagayama, Tomoko Seki, Maiko Takahashi & Yuko Kitagawa

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  1. Ayako Nakashoji
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  2. Tetsu Hayashida
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  3. Shigeo Yamaguchi
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Correspondence to Tetsu Hayashida.

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Nakashoji, A., Hayashida, T., Yamaguchi, S. et al. Comprehensive analysis of the homeobox family genes in breast cancer demonstrates their similar roles in cancer and development. Breast Cancer Res Treat 186, 353–361 (2021). https://doi.org/10.1007/s10549-020-06087-2

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