Targeting the HOX/PBX dimer in breast cancer.
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 HOXB1-HOXB9 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.
Oncology, Institute of Bioscience and Medicine, Faculty of Health and Medical Sciences, Leggett Building, University of Surrey, Surrey, GU2 7WG, UK. r.morgan@surrey.ac.uk
Richard
R
Morgan
Angie
A
Boxall
Kevin J
KJ
Harrington
Guy R
GR
Simpson
Cheryl
C
Gillett
Agnieszka
A
Michael
Hardev S
HS
Pandha
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos; D016158:Genes, p53; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000494:pharmacology / Q000633:toxicity; D055503:Protein Multimerization / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C522972:HXR9 peptide; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins