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angiogenic vasculature. In agreement with these findings, PR , HER2 ). Patients with HER2-positive metastatic
−
[77]
− [83]
in lung carcinoma BM a correlation between MMP2 and breast tumors are 2-4 times more likely to develop CNS
angiogenesis was also found. In this study tumors tumors than patients with HER2-negative disease and
[82]
[78]
expressing MMP2 display a more proliferating vasculature patients with triple negative breast cancer and basal like
at the tumor-brain interface compared to MMP2-negative breast cancer (BLBC) also appear to be at a high risk for
tumors, suggesting that MMP2 expression may be a key developing BM. [84]
player in this process by enhancing both invasion and
vascularization. The HER2/neu gene is amplified in 20-25% of primary
breast cancer cases; however, gene expression profiles can
Fibroblast growth factor receptor 1 (FGFR1) signaling has vary between the primary tumor and metastatic formations
repeatedly been described as a critical permissive factor for and therefore it could not be correct to assume that the HER2
distant spread of cancer cells through induction of EMT, status of the metastatic tumor reflects that of the primary
interaction with neural cell adhesion molecule neural tumor. Biopsies of metastases could provide essential
[85]
cell adhesion molecule and N-cadherin or upregulation informations in the case of HER2 expression discordance,
of osteopontin and matrix metalloproteases. FGFR1 thus redirecting therapeutic strategies by clinicians. It was
[79]
amplifications are common in squamous cell carcinoma and found that loss of HER2-positive status in metastatic tumors
rare in adenocarcinoma of the lung but a recent study found from patients with primary HER2-positive breast cancer is
enrichment of FGFR1 amplifications, not related to patients related to therapeutic treatments with chemotherapy with or
survival, in BM of NSCLC and adenocarcinomas (5-fold without trastuzumab and in addition, patients with HER2
more frequent than in primary tumors) suggesting a specific discordance between their primary and metastatic tumors
role of FGFR1 in metastasis formation. [79] have shorter OS. [85]

In order to identify new molecular features associated to Another study found that 243 genes were up or down-
BM formation, chromosomal copy number alterations regulated in brain metastatic cell lines, compared to the
in NSCLC samples was performed; selectively amplified primary tumor derived cell line and that the expression
[86]
regions of primary lung adenocarcinomas (5q35, 10q23 and of 17 genes was correlated with brain relapse. Interestingly,
17q23-24) were identifi ed as signifi cantly associated with the expression of these 17 genes in breast tumors was not
the development of early BM within 3 months after first associated with relapse to bones, liver or lymph nodes and
diagnosis of primary tumors. Interestingly, those regions the association with brain relapse was significant within ER-
were found to contain putative metastasis promoting tumours and in patients who received no adjuvant therapy.
genes, such as NeurL1B, ACTA2, FAS and ICAM2, but A sub-set of these 17 genes that includes prostaglandin-
[80]
the biological significance of these amplifi cations still synthesizing enzyme COX2, collagenase-1 (MMP1),
remains to be elucidated. angiopoietin-like 4, LTBP1 and FSCN1, the putative
metastasis suppressor retinoic acid receptor responder three
BREAST CANCER and heparin-binding EG plays fundamental roles in cell
extra-vasation and invasion and in general, in supporting
Breast cancer types are routinely classified on the basis of cancer cells migration and survival. [87-91]
clinical parameters (age, lymph node status, tumor size,
histological grade) and pathological markers that usually Among the genes upregulated in breast cancer BM, an
direct clinicians for the therapy [estrogen receptor (ER), important role is also played by the α2,6-sialyltransferase
progesterone receptor (PR), human epidermal growth factor (ST6GALNAC5) because its mRNA levels were found to
receptor 2 (HER2)]. During the last 15 years, 5 sub-types of be notably higher in brain metastatic cells than in parental,
breast cancer have been identified, on the basis of molecular primary tumor derived cell lines. Sialyltransferases
[86]
markers: luminal A, luminal B, HER2-enriched, basal-like are a family of at least 18 different intra-cellular Golgi
and claudin-low. [81] membrane-bound glycosyltransferases that catalyse the
addition of sialic acid to gangliosides and glycoproteins.
In patients with breast cancer BM are less common than Cell-surface sialylation has been implicated in cell-cell
bone or visceral metastases and frequently represent a late interactions and metastatic cells overexpressing the
[92]
event; nevertheless, up to 16% of metastatic breast cancer ST6GALNAC5 messenger, compared to the parental
patients develop clinically significant BM while autopsy cell lines, showa more marked adhesive behaviour to
studies showed that up to 30% of patients actually develop monolayers of human primary brain endothelial cells.
brain disease. [3,82] Conversely, ST6GALNAC5-knockdown decreased the
brain metastatic activity of BM derived cells. [86]
Several risk factors have been associated with the
development of BM in patients with metastatic breast Another gene implicated in BM is hexokinase 2 (HK2).
cancer, particularly the young age (35 or younger), HER2- HK2 is one of four members of the HK family that includes
enriched sub-type and triple-negative breast cancer (ER , HK1, HK2, HK3 and Glucokinase, enzymes involved
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦ 95