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

IntroductionTriple 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.Methods62 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).ResultsHIF-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).ConclusionsA 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.

Expression of Hypoxia-Inducible Factor 1α in Invasive Breast Cancer with Metastasis to Lymph Nodes: Correlation with Steroid Receptors, HER2 and EPO-R

“…Yehia et al in their study found that half of TNBC is linked with a marker of hypoxia (HIF-1α), but pointed out that this relationship is not only unique to TNBC, as similar findings were observed in the present study. Also Yehia et al demonstrated that half of cancers HER2(+) showed the expression of HIF-1α, and similar results were observed in the present study [30].…”

“…In our study, expression of HIF-1α was most often noted in cancers exhibiting expression of HER2 protein (57.14%). Similar results were obtained by Yehia et al (2015) finding in the whole group of breast cancer 39% of cancers that express HIF-1α (own research -36.2%), and lack of expression of HIF-1α found in 61% (respondents own -63.8%). Also showed the expression of HIF-1α at 50% TNBC (own research 42.9% TNBC), and showed the expression of HIF-1α at 50% of cancers that express HER2(+) (researches own 57.14%).…”

Pannexin1 Is Associated with Enhanced Epithelial-To-Mesenchymal Transition in Human Patient Breast Cancer Tissues and in Breast Cancer Cell Lines

“…A representative formalin-fixed paraffin-embedded (FFPE) tissue block from each case was obtained for molecular analyses. Negative controls were obtained from breast tissue of patients who underwent reduction mammoplasty [94]. The protocol of this study was approved by the American University of Beirut under the permission of the pathology departments at the American University of Beirut Medical Center and Hammoud Hospital University Medical Center (IRB PALM.…”

Targeting of the breast cancer microenvironment with a potent and linkable oxindole based antiangiogenic small molecule

“…Certainly, an important parameter to consider when treating BrCa with antiangiogenic agents is the reported drug induced tumor hypoxia (through upregulation of Hypoxia Inducible Factor, HIF) and an increase in cancer stem cells that promote drug resistance and disease progression [10]. However, a similar effect is also observed for cytotoxic agents [33] suggesting that hypoxia is a key feature in BrCa and combinational treatment regimes including an HIF inhibitor should be evaluated [34]. Thus, several reports justify that antiangiogenic therapy still holds a future in BrCa treatment [13].…”