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A Mouse Mammary Gland Involution mRNA Signature Identifies Biological Pathways Potentially Associated with Breast Cancer Metastasis

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

An Erratum to this article was published on 28 May 2009

Abstract

Mouse mammary gland involution resembles a wound healing response with suppressed inflammation. Wound healing and inflammation are also associated with tumour development, and a ‘wound-healing’ gene expression signature can predict metastasis formation and survival. Recent studies have shown that an involuting mammary gland stroma can promote metastasis. It could therefore be hypothesised that gene expression signatures from an involuting mouse mammary gland may provide new insights into the physiological pathways that promote breast cancer progression. Indeed, using the HOPACH clustering method, the human orthologues of genes that were differentially regulated at day 3 of mammary gland involution and showed prolonged expression throughout the first 4 days of involution distinguished breast cancers in the NKI 295 breast cancer dataset with low and high metastatic activity. Most strikingly, genes associated with copper ion homeostasis and with HIF-1 promoter binding sites were the most over-represented, linking this signature to hypoxia. Further, six out of the ten mRNAs with strongest up-regulation in cancers with poor survival code for secreted factors, identifying potential candidates that may be involved in stromal/matrix-enhanced metastasis formation/breast cancer development. This method therefore identified biological processes that occur during mammary gland involution, which may be critical in promoting breast cancer metastasis that could form a basis for future investigation, and supports a role for copper in breast cancer development.

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Abbreviations

AP-1:

activator protein 1

CI:

confidence interval

bHLH-Zip:

basic helix-loop-helix protein with leucine zipper

DCIS:

ductal carcinoma in situ

EGF:

epidermal growth factor

ER:

oestrogen receptor

ErbB2:

erythroblastic leukemia viral oncogene homologue 2

GC-RMA:

robust multi-array expression measure using GC-content information

GenMAPP:

gene map annotator and pathway profiler

GO:

Gene Ontology

HER2:

Human EGF receptor 2

HIF:

hypoxia-inducible factor

HOPACH:

hierarchical ordered partitioning and collapsing hybrid

HR:

hazard ratio

IGF-1:

Insulin-like growth factor

IGFBP5:

IGF-binding protein 5

LPS:

lipopolysaccharide

Neu:

neuro/glioblastoma derived oncogene homolog (avian)

PANTHER:

protein analysis through evolutionary relationships

PgR:

progesterone receptor

TGF:

transforming growth factor

VEGF:

vascular endothelial growth factor

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Acknowledgements

The authors would like to thank Drs David Flint and Pepper Schedin for very helpful discussions, and Dr Jennifer Richer for very valuable feedback. This work was funded by Breakthrough Breast Cancer through a programme grant to B. Gusterson, and the Dutch Cancer Society Grant NKB 2002–2575 to D.S.A. Nuyten and M.J. van de Vijver.

The complete datasets are available at http://conklinwolf.ucsf.edu/informatics/oncosplit.html.

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No competing interest declared.

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Correspondence to Torsten Stein.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s10911-009-9127-7

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Stein, T., Salomonis, N., Nuyten, D.S.A. et al. A Mouse Mammary Gland Involution mRNA Signature Identifies Biological Pathways Potentially Associated with Breast Cancer Metastasis. J Mammary Gland Biol Neoplasia 14, 99–116 (2009). https://doi.org/10.1007/s10911-009-9120-1

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