Expression of HIF-1α and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy.

Abstract

INTRODUCTION:

Triple negative breast cancer lacks estrogen, progesterone and epidermal growth factor receptors rendering it refractory to available targetedtherapies. TNBC is associated with central fibrosis and necrosis, both indicators of tumor hypoxia. Hypoxia inducible factor 1α is up-regulated under hypoxia and its expression is associated with induction of angiogenesis resulting in proliferation, aggressive tumor phenotype and metastasis. In this study we evaluate the potential use of HIF-1α as aTNBC-specific marker.

METHODS:

62 TNBC, 64 HER2+, and 64 hormone-receptors positive breast cancer cases were evaluated for central fibrosis and necrosis, HIF-1α, HIF-1β, VEGFR3, CD31 expression and microvessel density. RNA extraction from paraffin-embedded samples, followed by quantitative real-time polymerase chain reaction (qRT-PCR) evaluation of HIF-1α and VEGF transcripts was performed on 54 cases (18 from each subtype).

RESULTS:

HIF-1α protein was expressed in 35.5% TNBC, 45.3% HER2+and 25.0% ER+/PR+ (p = 0.055; χ2 test). PCRanalysis of subgroup of breast cancers, 84.2% expressed HIF-1α protein and its transcripts, while only 66.7% expressed VEGF transcripts simultaneously with the HIF-1α protein and its transcripts. Central fibrosis and necrosis was highest in TNBC (p = 0.015; χ2 test), while MVD was comparable among all groups (p = 0.928; χ2 test). VEGFR3 was highest in TNBC expressing HIF-1α. HIF-1β protein was expressed in 32.0% of HIF-1α(+), and in (44.3%) of HIF-1α(-) breast cancer cases (p = 0.033; χ2 test). Moreover, HIF-1α expression in cases with central fibrosis and necrosis was highest in the HER2+ followed by the TNBC (p = 0.156; χ2 test).

CONCLUSIONS:

A proportion of TNBC express HIF-1α but not in a significantly different manner from other breast cancer subtypes. The potential of anti-HIF-1α targeted therapy is therefore not a candidate for exclusive use in TNBC, but should be considered in all breast cancers, especially in the setting of clinically aggressive or refractory disease.

• Authors: Lamis Yehia, Fouad Boulos, Mark Jabbour, Ziyad Mahfoud, Najla Fakhruddin, Marwan El-Sabban
• Journal: PloS one (PLoS One) Vol. 10 Issue 6 Pg. e0129356 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26046764 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARNT protein, human
• Biomarkers, Tumor
• Hypoxia-Inducible Factor 1, alpha Subunit
• Platelet Endothelial Cell Adhesion Molecule-1
• Vascular Endothelial Growth Factor A
• Aryl Hydrocarbon Receptor Nuclear Translocator
• FLT4 protein, human
• Vascular Endothelial Growth Factor Receptor-3

Topics

• Adult
• Aged
• Aged, 80 and over
• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics, metabolism)
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Female
• Forecasting
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Immunohistochemistry
• Middle Aged
• Molecular Targeted Therapy (methods, trends)
• Neovascularization, Pathologic (genetics, metabolism)
• Platelet Endothelial Cell Adhesion Molecule-1 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-3 (genetics, metabolism)