title: 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: BACKGROUND
  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.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44195, United States of America.
authors.forename: Lamis
authors.initials: L
authors.lastname: Yehia
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Fouad
authors.initials: F
authors.lastname: Boulos
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Mark
authors.initials: M
authors.lastname: Jabbour
authors.affiliation: Department of Public Health, Weill Cornell Medical College, Doha, Qatar.
authors.forename: Ziyad
authors.initials: Z
authors.lastname: Mahfoud
authors.affiliation: Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Department of Pathology, Hammoud Hospital University Medical Center, Sidon, Lebanon.
authors.forename: Najla
authors.initials: N
authors.lastname: Fakhruddin
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
authors.forename: Marwan
authors.initials: M
authors.lastname: El-Sabban
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005544:Forecasting; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
chemical_list: C497396:ARNT protein, human; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3