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was evaluated . Knockdown of HIF-1α in Trastuzumab-resistant cells was observed to cause a decrease in the
[32]
proliferation of HIF-1α, just as the up-expression of HIF-1α in cells caused resistance to the anti-proliferative
effect of Trastuzumab, showing that there is a direct link between the levels of HIF-1αexpression and resistance
to Trastuzumab. HIF-1α up-regulates HES-1 expression, a negative regulator of the PTEN promoter, implying
that HIF-1α can modulate PTEN expression in Trastuzumab-resistant cells with the constitutive activation of
the STAT3 protein .
[32]
4-Hydroxynonenal (4-HNE) is produced in the lipid peroxidation of cells and is present at high levels in
invasive breast cancer cells. The role of 4-HNE in the stabilization of HIF-1α in breast cancer cells was
assessed by Li et al. . Sirtuin-1 (SIRT1) and Sirtuin-3 (SIRT3) are covalently modified by 4-HNE, leading to
[32]
SIRT3 deacetylase activity. SIRT3 was also observed to destabilize the HIF-1α protein and inhibit its activity.
Regulation of cell growth, invasion and expression of VEGF may be the result of the destabilization of the
HIF-1α protein by the inhibition of SIRT3, induced by 4-HNE. These results led researchers to conclude that
4-HNE is involved in resistance to chemotherapeutic drugs via up-regulation of HIF-1α .
[33]

Zhong et al. studied the role of HIF-1α in the regulation of radiation-induced autophagy in mammary
[34]
neoplasia cells. Michigan Cancer Foundation-7 (MCF-7) in cultures mimicking hypoxia had greater survival
of cells when exposed to ionizing radiation. Isogenic cells constitutively expressing HIF-1α small hairpin
RNA decreased the expression of HIF-1α and also the formation of colonies. This fact suggested that the
HIF-1α knockdown increased radiosensitivity.

Long non-coding RNAs (LncRNAs) are non-coding transcripts involved in the modulation of various
signaling pathways, acting as oncogenes or tumor suppressors during tumorigenesis . The urothelial
[35]
carcinoma-associated 1 (UCA1) lncRNA, which induces adriamycin resistance in MCF-7 cells, was used to
test for resistance to tamoxifen in breast cancer cells. Cells expressing UCA1 lncRNAs were transfected with
an up-expressing HIF-1α vector, and UCA1 lncRNA was found to be regulated in ER+ cells in a HIF-1α-
dependent manner . UCA1 expression was also observed to be increased by an miR-18 - HIF-1α feedback
[35]
loop.

HIF-1α INHIBITION AS THERAPEUTIC AGENT
As seen previously, the high expression of HIF-1a is associated with a worse prognosis and resistance
to antineoplastic treatments. The low expression of HIF-1α, by its turn, is linked to several metabolic
alterations, since it influences the regulation of other genes that are important in the process of metastasis of
breast cancer [36,37] . The low expression of HIF-1α leads to decreased expression of the Snail and twist-related
protein 1 (TWIST1) genes, signaled by transforming growth factor β1 (TGF-β1), a protein that stimulates cell
differentiation and proliferation that is known to regulate the EMT process in tumor cells . Both Snail and
[36]
TWIST1 are genes most commonly expressed in hypoxia. The silencing of HIF-1α led to the termination of
TGF-β-regulated breast cancer cell invasion . Reduced expression of HIF-1α increased apoptosis when on
[36]
serum starvation. At the same time, Caspase 3 fragments were identified with enhanced activity, indicating
that HIF-1α maintains cell growth and survival by inhibiting apoptosis . It was also observed that reduced
[38]
expression of HIF-1α inhibited TNBC migration and invasion ability . Thus, given the importance of the
[38]
role of HIF-1α in the development and progression of neoplasias, this gene has become the target of several
studies that have been carried out to identify or create HIF-1α inhibitors that could be used as therapeutical
agent, as can be seen in the studies below.

Brachyury is a transcription factor of the T-Box family characterized by a highly conserved DNA binding
domain called T-Domain, which is directly related with the progression of tumor cells . High Brachyury
[39]
expression was related to a significant increase in HIF-1α expression in MCF-7 and T47D cells. Akt/PTEN