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The matricellular protein CYR61 promotes breast cancer lung metastasis by
facilitating tumor cell extravasation and suppressing anoikis
#MMPMID27911269
Huang YT
; Lan Q
; Lorusso G
; Duffey N
; Rüegg C
Oncotarget
2017[Feb]; 8
(6
): 9200-9215
PMID27911269
show ga
Matricellular proteins play multiple roles in primary tumor growth, local
invasion and tumor angiogenesis. However, their contribution to metastasis and
the putative mechanisms involved are less well characterized. In ER-negative
human breast cancer, elevated expression levels of the matricellular protein
Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive
progression. Here, we investigated the role of CYR61 in breast cancer lung
metastasis using the triple negative human breast cancer cell lines MDA-MB-231
and SUM159. Silencing of CYR61 significantly decreased lung metastasis from
tumors orthotopically implanted in pre-irradiated or naive mammary tissue and
upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell
extravasation to the lung during the first 24 hours after tail vein injection. In
contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection
had no impact on lung metastasis formation. In vitro experiments revealed that
CYR61 silencing decreased cancer cell transendothelial migration and motility,
reduced CYR61 levels present at the cell surface and sensitized cancer cells to
anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under
non-adhesive conditions relied, at least partially, on ?1 integrin ligation and
AMPK? signaling while it was independent of AKT, FAK and ERK1/2 activation. Our
data provide the first evidence that CYR61 promotes breast cancer lung metastasis
by facilitating tumor cell extravasation and protecting from anoikis during
initial seeding to the lung. The uncovered CYR61-?1 integrin-AMPK? axis may serve
as a potential therapeutic target to prevent breast cancer metastasis to the
lung.
|*Anoikis
[MESH]
|*Cell Movement
[MESH]
|AMP-Activated Protein Kinases/metabolism
[MESH]
|Animals
[MESH]
|Cysteine-Rich Protein 61/genetics/*metabolism
[MESH]
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