The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen.

Abstract

INTRODUCTION:

The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy.

METHODS:

The expression of PHD1, PHD2 and PHD3 together with HIF-1α and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment.

RESULTS:

PHD1, PHD2 and PHD3 were detected in 47/179 (26.7%), 85/163 (52.2%) and 69/177 (39%) of tumours at baseline. PHD2 and PHD3 expression was moderate/strong whereas PHD1 expression was generally weak. There was a significant positive correlation between HIF-1α and PHD1 (P = 0.002) and PHD3 (P < 0.05) but not PHD2 (P = 0.41). There was a significant positive relationship between VEGF and PHD1 (P < 0.008) and PHD3 (P = 0.001) but not PHD2 (P = 0.09). PHD1, PHD2 and PHD3 expression was significantly increased after epirubicin therapy (all P < 0.000) with no significant difference in PHD changes between the treatment arms. There was no significant difference in response in tumours that expressed PHDs and PHD expression was not associated with survival.

CONCLUSIONS:

Although expression of the PHDs was not related to response or survival in patients receiving neoadjuvant epirubicin, our data provide the first evidence that these enzymes are upregulated on therapy in breast cancer and that the biological effects independent of HIF make them therapeutic targets.

• Authors: Stephen B Fox, Daniele Generali, Alfredo Berruti, Maria P Brizzi, Leticia Campo, Simone Bonardi, Alessandra Bersiga, Giovanni Allevi, Manuela Milani, Sergio Aguggini, Teresa Mele, Luigi Dogliotti, Alberto Bottini, Adrian L Harris
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 13 Issue 1 Pg. R16 (Feb 03 2011) ISSN: 1465-542X [Electronic] England
• PMID: 21291529 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Hypoxia-Inducible Factor 1, alpha Subunit
• Vascular Endothelial Growth Factor A
• Tamoxifen
• Epirubicin
• Prolyl Hydroxylases
• EGLN1 protein, human
• EGLN2 protein, human
• EGLN3 protein, human
• Hypoxia-Inducible Factor-Proline Dioxygenases

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, enzymology, genetics)
• Epirubicin (pharmacology, therapeutic use)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases (metabolism)
• Prognosis
• Prolyl Hydroxylases (genetics, metabolism)
• Tamoxifen (pharmacology, therapeutic use)
• Vascular Endothelial Growth Factor A (metabolism)