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Page 4 of 11 Peiró et al. J Cancer Metastasis Treat 2019;5:49 I http://dx.doi.org/10.20517/2394-4722.2018.109

HIF-1α expression in breast cancer cells influences AKT and ERK pathways, which promote angiogenesis,
further worsening the patient’s prognosis . Another transcription pathway that was also seen to be more
[10]
expressed along with the high expression of HIF-1α was the PI3K/AKT pathway, which is important in
signaling proliferation, invasion, angiogenesis, etc. .
[23]
HIF-1α expression is directly related to the expression of VEGF [16,24] and Axl (Tyrosine-kinase receptor),
which is described as being more expressed in a hypoxic environment and acts in much the same way as
HIF-1α (angiogenesis, metastasis, invasion, etc.). It was also seen that both aided in the regulation of EMT,
which in turn is an important step in the progression and metastasis of cancers .
[24]

When the increase of HIF-1α expression is regulated by lysophosphatidic acid receptor 2, it has been
associated with increased proliferation, migration and cell invasion parameters [15,24] . An increase in the
expression of the EZH2 gene (enhancer of zeste homologue 2, known to act on the aggressive profile of
tumors) is completely linked to that of HIF-1α . Patients expressing high levels of HIF-1α and EZH2 had
[25]
worse prognoses, data showing that both can potentially lead the individual to death . A direct relationship
[25]
between the high HIF-1α expression and a greater p53 expression has also been described, which is an
aggravating factor for the progression of breast cancer, since the loss of p53 function implies an increase in
vascular endothelial growth factor (VEGF) expression mediated by HIF-1α, and consequently, increased
angiogenesis .
[13]
An assessment of HIF-1α and nuclear factor-kappa B (NF-κB) levels as prognostic factors in breast cancer,
related to the sub-type of cancer and overall survival (OS) was done by Rajkovic-Molek et al. . Activation
[26]
of HIF-1α and NF-κB (detected by nuclear staining) was found in 41% and 31% of tumors, respectively. In
addition, HIF-1α was related to worse OS, making its expression an unfavorable prognostic factor .
[26]

HIF-1α IN DRUG RESISTENCE
The high expression of HIF-1α has been related to worse prognosis not only by the pathways affected that lead
to more aggressive tumors, but also by its association with resistance to hormone, chemo - and radiotherpies
in breast cancer [27,28] .

Tamoxifen is a drug which acts as an estrogen receptor antagonist, widely used in the treatment of breast
cancer, as well as in prevention in women who are prone to develop breast cancer . Lactate generated through
[29]
cell fermentation in breast cancer (mediated by HIF-1α and the Warburg effect) is related to high rates of
resistance to Tamoxifen, and can therefore be a marker of resistance to treatment [29,30] . HIF-1α expression
inhibits estrogen receptor α (ERα), which contributes to Tamoxifen resistance and a worse prognosis. Tumors
expressing HIF-1α along with ERα were observed to have a much more aggressive profile . Letrozole, in turn,
[29]
is an aromatase inhibitor, a class of drugs used to treat ER positive breast neoplasms . That the non-hypoxic
[31]
expression of HIF-1α mediated the resistance to Letrozole effected by HER2 was also seen. HIF-1α protein
synthesis increases when activation of phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin
(mTOR) pathway by HER2 occurs in long term letrozole-treated cells. As a result, HIF-1α up-regulates the
expression of breast cancer resistant protein, which contributes to resistance to Letrozole . HIF-1α is also
[31]
involved in AI resistance in acquired cases and/or in de novo cases, showing a potential therapeutic target for
resistance to Letrozole and other AIs.

Trastuzumab is a monoclonal antibody against the HER2 domain, one of the most commonly used drugs
for the treatment of HER2+ breast cancers. The induction of resistance to Trastuzumab in breast cancer cells
through the activation of the signal transducer and activator of transcription protein (STAT3) pathway/HIF-1α/
hairy and enhancer of split-1 (Hes-1) leading to a down-regulation of phosphatase and tensin homolog (PTEN)