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Page 2 of 15 Mohamedi et al. J Cancer Metastasis Treat 2019;5:37 I http://dx.doi.org/10.20517/2394-4722.2018.81

Conclusion: Our results suggests that the interaction between ADAMTS-1 and fibulin-1 induces a pronounced anti-
tumoral effect.

Keywords: ADAMTS-1, fibulin-1, cell migration, cell proliferation, breast cancer, MCF-7, MDA-MB-231

INTRODUCTION
The extracellular environment is a dynamic niche in which multiple molecular interactions occur that
govern cell fate. Several families of extracellular proteins function in this molecular dance, influencing cell
[1,2]
properties and thus regulating either physiological or pathological processes . In addition, stromal cells are
considered especially important in the extracellular environment as they induce extracellular modifications
[3]
that can promote dysfunction in processes such as in cancer progression .

In general, proteases are considered to be responsible for altering tissues and initiating the extracellular
remodeling of tissues. Among proteases, members of the ADAMTS family have been widely implicated
in different steps of cancer development. The ADAMTS family consists of 19 members, all of which have
several domains, including a metalloprotease, a disintegrin and a variable number of thrombospondin
[4]
motifs, which allow them to interact with different components of the extracellular matrix (ECM) .
ADAMTS-1 was the first identified member of this family of matrix metalloproteases due to its association
[5]
with inflammation processes . Since its discovery, ADAMTS-1 has been described to participate in several
[6-8]
other processes, such as organogenesis, vessel formation and ovulation . The participation of ADAMTS-1
in cancer is underlined by its implication in some of the most important features of cancer development and
[9]
progression . Thus, ADAMTS-1 has positive effects on cell survival, invasion and migration processes and,
in general, does not participate in cell proliferation [10,11] . Furthermore, ADAMTS-1 promotes angiogenesis in
breast xenografts, but it is also able to inhibit angiogenesis in lung and hepatic metastasis as well as in other
cell-based angiogenic experiments [11,12] .

Several studies provide conflicting associations of ADAMTS-1 with breast cancer; ADAMTS-1 has
been reported to be both a pro- and anti-tumorigenic factor [10,13-15] . This dual function of ADAMTS-1
depends on the conditions in which the ADAMTS-1 pathway is functioning, i.e., microRNAs such as
miR-365 or peroxisome proliferator-activated receptor (PPARδ) [16,17] . The tumor promotion or tumor
inhibition properties associated with ADAMTS-1 can also depend on the fragmentation of ADAMTS-1
[18]
or the interactions of ADAMTS-1 with other components of the ECM . One of the known partners of
ADAMTS-1 in the ECM is fibulin-1; the interaction of these two proteins was described as a result of a yeast
two-hybrid screen for potential interactions of ADAMTS-1. As a result of this interaction, the proteolytic
activity of ADAMTS-1 towards aggrecan is increased; thus, fibulin-1 is considered a cofactor of ADAMTS-1
[19]
aggrecanase activity .
[20]
Fibulin-1 was the first identified member of the fibulin family of matrix proteins . The members of
this family each contain a fibulin-like domain at the carboxy terminal of the protein. The fibulin family
consists of seven members of different lengths that contain different motifs with varying functions, such
as anaphylatoxin domains (fibulin-1 and fibulin-2), epidermal growth factor ( EGF)-like modules (fibulin-3
and fibulin-4), thrombospondin-like and von Willebrand factor domains (fibulin-6) or a sushi domain
[21]
(fibulin-7) . In particular, fibulin-1 and fibulin-2 are closely related and characterized by the presence of
anaphylatoxin and calcium-binding EGF (cbEGF) modules. However, only fibulin-2 contains two additional
modules: cysteine (cys)-rich and cys-free domains. In addition, fibulin-1, fibulin-2, fibulin-3, fibulin-4 and
fibulin-5 are considered elastogenic fibulins since they are important components of elastic fibers that are
particularly abundant in the dermis, lungs and arterial walls [21,22] .