IJUP08 - Universidade do Porto

P-cadherin: role in breast cancer cell migration and invasion
Ribeiro AS 1 , Paredes J 1,2 , Correia AL 2 , Schmitt F 1,2
1 IPATIMUP, Institute of pathology and molecular immunology from University of Porto;
2 School for Health and Sciences, Minho University
Cadherins are calcium-dependent glycoproteins that mediate cell-cell adhesion, presenting
a characteristic pattern of distribution in human tissues. In mammary gland, P-cadherin is
only expressed in myoepithelial cells; however, its expression has been reported in breast
carcinomas, where it is associated with high-grade histological tumours and with poor
patient survival [1-3].
In order to elucidate the role of P-cadherin in breast cancer progression, we aimed to
clarify the capabilities acquired by breast cancer cells, such as motility, migration and
invasion, using as a model a breast cancer cell line (MCF-7/AZ) which was retrovirally
transduced with human P-cadherin (MCF-7/AZ.Pcad).
Using a wound healing assay, we demonstrated that P-cadherin overexpression was able to
promote breast cancer cell migration, which was suppressed by a blocking antibody against
this protein. Also cell motility, measured by time-lapse microscopy, was increased, and it
was strongly associated with the formation of actin filopodia and lamellipodia, whereas its
siRNA-specific silencing reduced the presence of these membrane protrusions.
Besides our group has shown previously, that P-cadherin overexpression in breast cancer
cells promotes in vitro cell invasion [4], in the present study we proved that this effect is Pcadherin
specific, since invasion was decreased to basal levels upon the inhibition of this
molecule. We then considered that this effect could be due to proteases secretion to the
medium, and in fact MMP-1 and MMP-2 activity and expression showed to be increased in
MCF-7/AZ.Pcad cells, as well as a soluble P-cadherin fragment. Furthermore, when
parental cells where treated with the conditioned medium recovered from P-cadherin
overexpressing cells, cell invasion was promoted, implying that MCF-7/AZ.Pcad cells
secrete proteins to the medium that should be involved and facilitate cell invasion.
Taken together, this work presents, a possible cellular mechanism explaining why Pcadherin
expression is associated with a more aggressive phenotype and a poor patient
survival in breast carcinomas.
References
[1] Paredes J, Milanezi F, Viegas L, Amendoeira I, Schmitt FC (2002), P-cadherin expression
is associated with high-grade ductal carcinoma in situ of the breast, Virchows Arch 440:
16-21, 2002
[2] Paredes J, Milanezi F, Viegas L, Amendoeira I, Schmitt FC (2002), P-cadherin expression
is associated with high-grade ductal carcinoma in situ of the breast, Virchows Arch 440:
16-21, 2002
[3] Paredes J, Albergaria A, Oliveira JT, Jerónimo C, Milanezi F, Schmitt FC (2005), Pcadherin
overexpression is an indicator of clinical outcome in invasive breast carcinomas
and is associated with CDH3 promoter hypomethylation, Clin Cancer Res 11: 5869-5877,
2005
[4] Paredes J, Stove C, Stove V, Milanezi F, Van Marck V, Derycke L, Mareel M, Bracke M,
Schmitt F (2004), P-cadherin is upregulated by ICI 182,780 in breast cancer cells and
promotes invasion via its juxtamembrane domain, Cancer Res 64: 8309-8317, 2004.
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