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Page 6 of 18 Malone et al. J Cancer Metastasis Treat 2021;7:40 https://dx.doi.org/10.20517/2394-4722.2021.37

with the average duration of survival after diagnosis of brain metastases ranging from 6-16 months [3,23,24,44] .
Brain metastases are most common in TNBC and ERBB2 expressing breast cancers and are most likely to be
lethal in patients with TNBC [23-25,44,45] . Younger patients and those diagnosed with an increased tumor stage,
detection of lymph node metastases, greater than 2 metastatic sites other than the brain, or large tumor
diameter are more likely to form brain metastases [17-22,46] . A study performed using patient data from the
Metropolitan Detroit Cancer Surveillance System revealed that African American women were more likely
to form distant metastases in the brain . However, a study using patient data from the SEER database
[47]
[46]
showed that patient race or ethnicity did not appear to affect the likelihood of forming brain metastases .
Another study that included 204,941 patients reported that as expected the TNBC subtype was associated
with higher likelihood of de novo metastases occurring in the brain in both non-Hispanic-Black (n = 36) and
non-Hispanic-White patients (n = 92), with higher percentages among non-Hispanic-Black patients (38.9
vs. 26.1). Surprisingly, the survival of those patients was on average 8 months for the non-Hispanic-Black
patients and 6 for the non-Hispanic-White patients .
[48]

DORMANCY
The phase of dormancy is very difficult to model in an experimental setting, as the majority of carcinoma
cells selected are metastatically aggressive. The theory that underlies exit from dormancy implicates a
balance between active metastasis initiating cells and antagonistic immune surveillance. The dormant
cancer cells receive growth-inhibitory signals in the host microenvironment, bypassing TGFβ1 brain-
[50]
specific signaling, secreting DKK1 to inhibit Wnt, and exhibit resistance to antimitotic therapy . Exit
[49]
from dormancy is not well understood, although changes in cell adhesion molecules, in neutrophil
[51]
extracellular traps, and autophagy genes have been documented to affect the process .
Using gene analysis approaches, seventeen genes have been described that promote metastatic tropism to
the breast cancer cells. Among them there are genes that may modify the cancer cell surface protein
[52]
expression, like α2,6-sialyltransferase ST6GALNAC5 , MMPs and chemokines or affect the ECM
[53]
protein expression , and these are reported to specifically drive metastasis to the brain. Once the cancer
[54]
cells enter the distant site of metastasis, two processes are initiated in an effort to overcome the hostility of
and co-opt the local environment and adapt metabolically: colonization and outgrowth of the cancer cells.
COLONIZATION
The development of BCBM depends on effectiveness of colonization of the perivascular space in the brain
and the local initial growth of the cancer cells. During the phase of colonization the cancer cells exhibit high
levels of oxidative stress and the formation of reactive oxygen species. Within the circulation the cancer cells
decrease their aerobic metabolism and oxidative phosphorylation, which is re-activated as the cells reach
their target organ location [55,56] . In that space (brain) the metastatic cancer cells interact with the brain
[57]
parenchymal microenvironment and eventually establish a metabolically-favorable tumor
[58]
microenvironment for metastasis (TME) . One of the events that lead to changes in the metabolism of the
proximal parenchyma is the restriction of blood flow and limited nutrient availability. Levels of glutamine
[59]
and glutamate are affected by these restrictions and the local metabolism is altered . A factor involved in
this metabolic change is the lymphoid enhancer-binding factor 1 (LEF1), which is frequently overexpressed
in cancer cells as they colonize the brain . LEF1 has recently been described to regulate glutathione
[60]
metabolism, thus protecting the cancer cells from undergoing apoptosis. Other reports have indicated that
cancer cells colonizing the CNS upregulate the expression of GABA receptors or GABA transporters as an
effort to be able to metabolize GABA, which is abundantly available in the CNS, as a source for protein
[61]
synthesis .