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Deregulated homeobox gene expression in cancer: cause or consequence?

Nature Reviews Cancer volume 2, pages 777–785 (2002)Cite this article

Key Points

Summary

  • Although deregulated homeobox gene expression was originally associated with oncogenic activities, it is now apparent that homeobox genes might be lost as well as gained in cancer, and their corresponding activities might be tumour suppressing as well as tumour promoting. Although there are numerous examples of the deregulated expression of homeobox genes in association with cancer, there are far fewer cases of causal links between these aberrant expressions and carcinogenesis.

  • Many examples of deregulated homeobox gene expression in cancer conform to a simple rule: homeobox genes that are upregulated in cancer are normally expressed during development and/or in undifferentiated cells, whereas homeobox genes that are downregulated in cancer are normally expressed in adulthood and/or in differentiated tissues.

  • Several examples exist in which homeobox genes impinge on the cell cycle, indicating that deregulation of cell-cycle control might be a common mechanism by which aberrant homeobox gene expression contributes to carcinogenesis.

  • Homeobox genes that are downregulated in cancer share several features, including tissue specificity and epigenetic loss of function.

  • Based on their unique features with respect to their expression and function, homeobox genes are best described as 'tumour modulators' rather than oncogenes or tumour-suppressor genes.

Abstract

Homeobox genes comprise a large and essential family of developmental regulators that are vital for all aspects of growth and differentiation. Although many studies have reported their deregulated expression in cancer, few studies have established direct functional roles for homeobox genes in carcinogenesis. Nonetheless, most cases of deregulated homeobox gene expression in cancer conform to a simple rule: those that are normally expressed in undifferentiated cells are upregulated in cancer, whereas those that are normally expressed in differentiated tissues are downregulated in cancer.

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Figure 1: Modes of regulating homeoprotein activity.
Figure 2: Homeobox proteins have both a positive and negative effect on the cell cycle.
Figure 3: The relationship between homeobox gene expression and epithelial development and carcinogenesis.

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Acknowledgements

I would like to thank B. McGinnis, A. Rabson, A. Shatkin, M. Shen, R. Stewart, A. Stock and E. White for comments on the manuscript. The diagram of the homeodomain bound to DNA was provided by R. Ebright. Research in my laboratory is supported by the National Cancer Institute and the Department of Defense.

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Authors and Affiliations

  1. Departments of Medicine and Neuroscience, Centre for Advanced Biotechnology and Medicine, The Cancer Institute of New Jersey, UMDNJ–Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, 08854, New Jersey, USA

    Cory Abate-Shen

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Cancer.gov

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colon cancer

colorectal cancer

epithelial cancer

leukaemia

myeloid leukaemia

prostate cancer

LocusLink

CDKN1A

CDX2

Cdx2

cyclin D1

Engrailed

HOX11

HOXA5

HOXA9

HOXB7

HOXB9

HOXD9

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Nkx3.1

NUP98

OTX2

PAX5

Pten

RB

TP53

OMIM

T-cell acute leukaemia

FURTHER INFORMATION

Homeobox home page

Glossary

HOMEOBOX

An evolutionarily conserved 180-base-pair sequence motif that is located in a large number of known or predicted genes that function as developmental regulators.

HOMEOPROTEINS

The proteins that are encoded by homeobox genes.

HOMEOTIC GENES

Mutations of these Drosophila genes result in homeotic mutations — the conversion of one body part to another. Homeotic genes were identified as part of a hierarchy of genes that control Drosophila development. Other classes of genes in this hierarchy, such as the gap, pair-ruled and segment polarity genes, also include homeobox genes.

HOMEODOMAIN

The 60-amino-acid protein domain encoded by the homeobox.

PARALOGOUS HOX GENES

Refers to genes located in the same position on the four HOX clusters. In general, paralogous HOX genes (for example HOXA9 and HOXB9) are more similar to each other than to adjacent genes on the same HOX cluster (for example, HOXA9 and HOXA10).

EPITHELIAL–MESENCHYMAL INTERACTIONS

Describes the reciprocal signalling between epithelial and mesenchymal tissue layers during embryogenesis. Epithelial–mesenchymal interactions are essential for the formation of many organs.

ALVEOLAR RHABDOMYOSARCOMA

A soft-tissue tumour with muscle differentiation occurring in children.

PARAXIAL MESODERM

The tissue that gives rise to the somites during development.

BASIC FIBROBLAST GROWTH FACTOR

(bFGF). A mitogenic growth factor that is widely utilized during development.

ADENOMATOUS INTESTINAL POLYP

A pre-malignant lesion that is a presumed precursor of colorectal cancer.

HAPLOINSUFFICIENCY

Loss or mutation of a single allele results in a detectable phenotype. Although the classic description of tumour-suppressor genes presumes inactivation of two alleles, there are now several examples in which loss or mutation of a single allele contributes to tumorigenicity77.

MIN MICE

Mice that have a mutation of the tumour-suppressor gene adenomatous polyposis coli (Apc). These mice are prone to develop intestinal polyps.

EPIGENETIC INACTIVATION

Alteration in gene activity that influences the phenotype without affecting the genotype. Examples are promoter methylation and post-transcriptional regulation.

PROSTATIC INTRAEPITHELIAL NEOPLASIA

(PIN). Pre-malignant lesions that are presumed precursors of prostate cancer.

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Abate-Shen, C. Deregulated homeobox gene expression in cancer: cause or consequence?. Nat Rev Cancer 2, 777–785 (2002). https://doi.org/10.1038/nrc907

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