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Page 12 of 15 Mohamedi et al. J Cancer Metastasis Treat 2019;5:37 I http://dx.doi.org/10.20517/2394-4722.2018.81

DISCUSSION
ECM proteins can be considered as important players in tissue homeostasis as it is considered the cellular
component. Interactions among different components of the ECM have crucial roles in normal and
pathological processes such as bone remodeling or tumor development [1,39] . The components of the ECM that
contain multiple motifs within the same protein unit are good candidates to establish various interactions
and build bridge connections between cells and other components of the ECM. Such is the case for the
members of two extracellular families of proteins, the fibulins and ADAMTSs [4,21] . Members of both families
have been associated with cancer development and progression and have been reported on many occasions
to interact with other components of the ECM, acting as pro- or anti-tumor agents [18,23] .

Fibulin-1 has been previously described to be an ADAMTS-1 cofactor and to stimulate the proteolytic
activity of ADAMTS-1 towards aggrecan and versican [19,40] . Herein, we have been able to describe the
significance of this fibulin-1/ADAMTS-1 interaction in the proliferation, migration and invasion properties
of breast cancer cell lines. Overall, our data support the idea that ADAMTS-1 is a pro-tumor agent in breast
cancer, whereas fibulin-1 is able to block this effect and acts as an anti-tumor agent. We have been able to
show that the presence of both proteins reduces the migration and invasion properties of two breast cancer
cell lines, MCF-7 and MDA-MB-231. The participation of ADAMTS-1 in cancer has been associated with
mammary tumor growth and progression to metastasis in the MMTV-PyMT model in an Adamts1-/-
[10]
background , whereas it has also been reported to be a tumor suppressor gene through proteolysis of
[41]
nidogen-1 and nidogen-2 in an HEK293T tumor xenograft assay . In our study, ADAMTS-1 expression was
not detected by tissue array analysis in samples of different stages of breast cancer. Additionally, the Kaplan-
Meier plots reflect the absence of an influence of ADAMTS-1 on expected patient overall survival. However,
the ectopic expression of ADAMTS-1 in breast cancer cell lines increased the tumorigenic potential of these
cell lines in terms of proliferation, migration, invasion and mammosphere formation. Initially, breast cancer
[42]
profiles showed the downregulation of ADAMTS-1 in malignant tumors compared to normal tissues .
However, other studies indicated the participation of ADAMTS-1 in aiding breast cancer development [10,11,13,43] .
Thus, the participation of ADAMTS-1 in breast cancer development and progression might depend on
substrates it is able to act upon, such as versican to facilitate spreading of tumor cells or semaphorin 3C,
which is known to promote metastatic potential of breast cancer cells [10,44] . Interestingly, ADAMTS1 was
the third most overexpressed gene in highly metastatic MDA-MB-231 clones, and the knockdown of
ADAMTS-1 in these clones regressed disease spread and reduced secondary tumor burden [45,46] . The effect
of this protein might also be dependent on which cell type produces and secretes ADAMTS-1, similar to the
[15]
paracrine effect of breast cancer cells over cancer-associated fibroblasts of the vicinity . Finally, the impact
of ADAMTS-1 might also depend on other ECM proteins that interact and bind with ADAMTS-1 and, as
result, are able to modulate ADAMTS-1 activity.

The fact that fibulin-1 has been described as an ADAMTS-1 cofactor able to modulate ADAMTS-1 activity
further implies the roles of both proteins in tumor development.

Fibulin-1 can interact with various ECM components, including known ADAMTS-1 substrates, such as
nidogen-1 and versican [2,21,27] . Fibulin-1 has also been implicated in cellular transformation and, similar
to ADAMTS-1, can behave as both a tumorigenic factor or tumor suppressor depending on the tissue
[23]
environment . Our results showed that the ectopic expression of fibulin-1 in breast cancer cell lines was
able to block the tumorigenic properties of these cell lines. Furthermore, fibulin-1 expression was able
to dramatically block these properties even in the presence of ADAMTS-1. Similar properties have also
been described in our laboratory in the interaction of two related components of the ECM, fibulin-2 and
ADAMTS-12. In this interaction, the expression of ADAMTS-12 alone exerted pro-tumoral activities,
[47]
whereas the coexpression of both ADAMTS-12 and fibulin-2 showed an important anti-tumoral effect .