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attenuation of RAS activation and mitogen-activated protein kinase (MAPK) activity and contributes to
tumor progression through weakened anti-RAS activity . In periods of hypoxia, reactive oxygen species
[12]
accumulation activates PI3k/Akt (Protein-kinase B) and MAPK/ERK (extracellular signal-regulated kinase)
pathways, essential for the maintenance of carcinogenesis, tumor angiogenesis and activation of HIF-1α.

PROGNOSIS VALUE OF HIF-1α EXPRESSION
Several genes are influenced by HIF-1α expression. In addition to the high expression of HIF-1α being
directly associated with tumor growth rate, metastatic potential, and consequently to the poor prognosis of
patients, it is also associated with tumor progression, since as the cancer stage advances, HIF-1α expression
increases . Thus, the possibility of using HIF-1α as a prognostic marker has already been discussed by
[13]
several authors [14-16] .

HIF-1α up-regulates Snail expression - a gene involved in induction of the epithelial-mesenchymal
transition (EMT) - promoting increased migration and aggressiveness of breast cancer cells. HIF-1α
together with Snail are responsible for the down-regulation of E-Cadherin expression, promoting EMT .
[17]
After inhibiting HIF-1α and Snail expression in triple negative breast cancer (TNBC) cells by adding small
doses of farnesyltransferase inhibitors, the following mRNA levels of HIF-1α expression pathway genes
were also decreased: Snail, glucose transporter 1 (GLUT1), pyruvate dehydrogenase kinase 1 and lactate
dehydrogenase A, all involved in the metabolism of hypoxia.

There is also a correlation between HIF-1α protein expression and the erythropoietin receptor protein in
aggressive breast cancer samples, which leads to the worsening of the cases, since both play an important
role in angiogenesis . γ-secretase is an intramembranous protease that cleaves transmembrane proteins .
[18]
[19]
HIF-1α containing the γ-secretase complex also contributes to the migration and invasiveness phenotype
of breast cancer cells. Another gene that is influenced by HIF-1α is heregulin, a growth factor that binds
to Erb-B2 receptor tyrosine kinase 3 (ErbB3) and ErbB4 receptors with a known role in cell proliferation,
survival, motility and tumorigenesis . According to the authors, stimulation of the ErbB3 receptor
[20]
and the activation of the P-Rex1/Rac1 pathway via induction of C-X-C Motif Chemokine Receptor 4 are
transcriptionally mediated by HIF-1α.

In breast neoplasms, SETD8, a methyltransferase that methylates H4K20, along with a transcription factor
related to cancer progression, has the function of regulating the increase and of N-Cadherin expression
and the decrease of E-Cadherin . This modulation would be responsible for the epithelial-mesenchymal
[21]
transition (EMT) phenotype, which increases the invasive potential of breast cancer cells. An interaction
between STED8 and HIF-1α was identified, as well as co-localization in the human embryonic kidney 293T
and MDA-MB-231 cell nuclei, indicating that they interact with each other. STED8 was seen to slightly
regulate HIF-1α expression, and STED8 silencing increased the acetylation and hydroxylation of HIF-1α,
demonstrating that STED8 plays a role in the stabilization of HIF-1α. It was also found that STED8 and
HIF-1α expression in patients with TNBC and HER2+ breast cancer were higher than in the Luminal A and
Luminal B molecular profile .
[21]
Interleukin-17 (IL-17) is a cytokine produced by T Helper lymphocytes associated with inflammatory
diseases that has also been related to onset, development and metastasis of tumors . IL-17 can modulate
[22]
the expression of some genes in breast cancer cells by altering their adhesion properties through pathways of
expression including that of HIF-1α. Tumor necrosis factor α (TNF-α), in turn, is a cytokine associated with
cell survival, apoptosis, inflammation and immunity . In addition, TNF-α regulates the expression of cell
[22]
adhesion proteins, which aid in the determination of a metastatic phenotype in tumor cells. Increased levels
of HIF-1α were also found in groups of cells treated with IL-17 and TNF-α in a dose-dependent manner .
[22]