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Breast Cancer Research and Treatment

, Volume 136, Issue 2, pp 389–398 | Cite as

Targeting the HOX/PBX dimer in breast cancer

  • Richard Morgan
  • Angie Boxall
  • Kevin J. Harrington
  • Guy R. Simpson
  • Cheryl Gillett
  • Agnieszka Michael
  • Hardev S. Pandha
Preclinical Study

Abstract

The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.

Keywords

Breast cancer SKBR3 MCF7 HXR9 HOX PBX 

Notes

Acknowledgments

The authors would like to thank the Guy’s and St Thomas’ (GST) Breast Tissue and Data Bank, London, UK for providing the patient samples used in this study, and the patients who agreed to contribute to this data bank. The study was in part supported by a grant from the Breast Cancer Campaign to RM. The experiments carried out comply with the laws of the United Kingdom.

Conflict of interest

All authors declare no conflict of interest.

Supplementary material

10549_2012_2259_MOESM1_ESM.eps (143 kb)
Online resource 1 Changes in expression of HXR9 target genes in SKBR3 cells. The relative expression of target genes are shown as a normalized intensity value (Log10), blue lines represent targets that increase expression in response to HXR9 compared to untreated cells [Unt], while the red lines represent targets that are repressed by HXR9 (EPS 142 kb)
10549_2012_2259_MOESM2_ESM.eps (205 kb)
Online resource 2 Distribution of HOX/PBX consensus sites in the promoter regions of the 20 most responsive HXR9 target genes. Possible HOX / PBX consensus binding sites are shown shaded according to the number of nucleotides that match the consensus (out of a maximum of 10). *Multiple consensus sites that overlap each other (EPS 205 kb)
10549_2012_2259_MOESM3_ESM.eps (261 kb)
Online resource 3 The mean expression values of HOX genes HOXB1 through to HOXB9 in primary tumors. Tumors were grouped according to (a) histopathological type, (b) estrogen receptor (ER) status, (c) spread to nodes as determined by pathology, (d) 5 year survival, (e) grade (G2, grade 2; G3, grade 3), (f) whether tumors were from the left or right breast, (g) progesterone receptor status (PR), and (h) HER2 status. Error bars show the SEM (EPS 260 kb)
10549_2012_2259_MOESM4_ESM.doc (101 kb)
Online resource 4–6 (DOC 101 kb)

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Richard Morgan
    • 1
  • Angie Boxall
    • 1
  • Kevin J. Harrington
    • 2
  • Guy R. Simpson
    • 1
  • Cheryl Gillett
    • 3
  • Agnieszka Michael
    • 1
  • Hardev S. Pandha
    • 1
  1. 1.Oncology, Institute of Bioscience and MedicineFaculty of Health and Medical Sciences, Leggett Building, University of SurreySurreyUK
  2. 2.Targeted Therapy Team, Chester Beatty LaboratoriesThe Institute of Cancer ResearchLondonUK
  3. 3.Guy’s & St Thomas’ Breast Tissue & Data BankKing’s College LondonLondonUK

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