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Page 2 of 11 Peiró et al. J Cancer Metastasis Treat 2019;5:49 I http://dx.doi.org/10.20517/2394-4722.2018.109

growth factors, sustained angiogenesis, limitless replication potential, and tissue invasion/metastasis . To
[2]
proliferate, tumors must form their own vascular network and blood supply, which is due to the influence
of tumor angiogenesis factors. However, the new vascular network that is formed differs from that found
in healthy tissues because it presents a series of structural and functional alterations. These alterations may
interfere with the adequate supply of blood and oxygen, leading to hypoxia, a state in which the organism is
functioning with reduced and/or no oxygen supply . In order for the cancer to prevent its metabolism from
[3]
being diminished or ceased in this situation, a family of transcription factors called hypoxia-induced factors
(HIF) is activated.

HIF is known to act on hematopoiesis, angiogenesis, apoptosis, cell reproduction, cancer cell metabolism
among other functions . HIF-1α action is complemented by the transcriptional co-activator with PDZ-
[2-5]
binding motif (TAZ), activating different genes that are involved in the same cascade. Both HIF-1α and TAZ
play an important role in remodeling the extracellular matrix, one of the important steps for tissue invasion
to occur; these genes act as co-activators of each other, potentiating the expression of HIF-1α target genes .
[6,7]

HIF-1α is especially important in the metabolism of cancers, being part of several metabolic pathways that
cancers use, such as metabolism in hypoxia, angiogenesis, cell reproduction, etc. Thus, cancers with a high
rate of metastasis and recurrence - as is the case with breast cancer - have their physiology strongly linked
to HIF-1α. Based on that, this review sought to group the most recent experimental studies on the role that
HIF-1α plays in the development and progression of breast cancer - one of the most incident and deadly
cancers worldwide - resistance to conventional treatments, as well as proposals for new treatments based on
its expression and/or inhibition.

HIF-1α MODULATION UNDER HYPOXIA
The genes in HIF family are composed of two subunits: HIF-1α (or one of its isoforms, HIF-2α or HIF-3α)
and HIF-1β (which is expressed constitutively, acting on a range of transcriptional systems) . The HIF-1α
[8]
subunit, when in normoxia, is rapidly degraded via the 26S ubiquitin-proteasome pathway by the von Hippel-
Lindau tumor suppressor protein; in situations of hypoxia, however, it has increased activity .
[2-4]
Under periods of normoxia, proline residues of HIF-1α are hydrolyzed by prolyl-4-hydroxylases. Hydroxylated
HIF-1α is then recognized by VHL and ubiquitinated by the E3 ubiquitin-protein ligase complex. After, its
proteasomal degradation occurs . Breast cancer grows very rapidly and usually the tumor microenvironment
[9]
has reduced oxygen distribution . In situations of hypoxia, hydroxylation of HIF-1α does not occur, after
[10]
which it is translocated and accumulates in the nucleus, where it binds to HIF-1β; the HIF-1α/HIF-1β complex
binds to hypoxia-response element, adhering to hypoxia target genes such as vascular endothelial growth
factor receptor (VEGF) and insulin-like growth factor 2 (IGF-2), stimulating angiogenesis and proliferation .
[9]
Inhibition of HIF-1α generated inhibition of signaling by VEGF/VEGFR2 factors, which in turn prevented
angiogenesis .
[10]
A model of HIF-1α modulation in hypoxia involves receptor of activated protein C kinase-1 (RACK1) and
heat shock protein-90 (HSP90) . In it, human rhomboid family-1 (RHBDF1) controls the competition
[11]
between RACK1 and HSP90 for binding to HIF-1α. The interaction between RACK1 and HIF-1α results
in its degradation, however prior to that RHBDF1 binds to RACK1, giving way for HIF-1α to bind to
HSP90, resulting in its stabilization. This model would explain the high levels of HIF-1α, Rack1, HSP90 and
RHBDF1 in various cancer cells, including breast cancer. This facilitation of HIF-1α activity as a result of the
action of RHBDF1 would also explain the relationship between the high protein level of RHBDF1 in distant
metastases and lymph nodes .
[11]
The RAS protein activator 1 (RASAL1) protein is known to be involved in the progression of hypoxia
resistance in breast cancer cells. The increase of intracellular Ca ions stimulates RASAL1, which leads to
2+