Review Article | Published:

S100 proteins in cancer

Nature Reviews Cancer volume 15, pages 96109 (2015) | Download Citation

Abstract

In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.

Key points

  • The S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable.

  • S100 family members function as intracellular Ca2+ sensors and extracellular factors.

  • Chromosomal alterations, mutations and/or translocations in S100 genes are rare in human cancers. Nonetheless, dysregulation of multiple S100 proteins is a common occurrence in individual human cancers and most often involves upregulation.

  • Each human cancer exhibits a distinctive S100 protein profile that can be both stage-specific and subtype-specific, as well as facilitate diagnosis, prognosis and/or drug response.

  • The modulation of S100 expression is a common downstream event in S100 signalling cascades, resulting in feedback loops that can sustain and exacerbate tumour progression.

  • The most common strategies for inhibiting S100 proteins exploit small molecules that block the hydrophobic cleft required for S100 proteins to interact with targets and elicit biological effects.

  • Inhibitors of two family members, S100B and S100A9, are in clinical trials for melanoma and prostate cancer, respectively.

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Acknowledgements

The authors apologize to the numerous colleagues whose important contributions could not be included in this Review owing to space limitations. The authors thank S. C. Almo and J. M. Backer for critical reading of this Review. The authors' research is funded by grants from the New York State Department of Health, Health Research Science Board (H11R-040; to A.R.B.), the National Cancer Institute (US National Institutes of Health; CA100324 to A.R.B. and CA107331 to D.J.W.), the Albert Einstein Cancer Center (NCI, NIH; CA013330), the Marlene and Stewart Greenebaum Cancer Center (NCI, NIH; CA134274) and the Center for Biomolecular Therapeutics, University of Maryland School of Medicine, USA (to D.J.W. and D.B.Z.).

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Affiliations

  1. Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

    • Anne R. Bresnick
  2. Center for Biomolecular Therapeutics and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, Maryland 20102, USA.

    • David J. Weber
    •  & Danna B. Zimmer

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Anne R. Bresnick or David J. Weber or Danna B. Zimmer.

Supplementary information

Glossary

Sub-states

Closely related interconverting conformational states that can be sampled by a protein under a given set of conditions.

GRS/A

An inbred mouse strain carrying the Mtv2a allele, which controls the expression of endogenous mouse mammary tumour virus and the early development of hormone-induced mammary tumours.

Lamellipodia

Transient cellular protrusions that form during cell migration.

Chemotactic migration

Directional cell migration in response to soluble extracellular ligands.

MMTV-polyoma middle T antigen

(MMTV-PyMT). A murine breast cancer model with expression of PyMT under the control of the mouse mammary tumour virus (MMTV) promoter.

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DOI

https://doi.org/10.1038/nrc3893

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