Breast cancer is the most common
carcinoma that metastasizes to bone.
Tumor-produced
parathyroid hormone-related protein (
PTHrP), a known stimulator of osteoclastic
bone resorption, is a major mediator of the osteolytic process in
breast cancer. We have previously shown that
PTHrP increases
breast cancer cell proliferation, survival, migration, and pro-invasive
integrin alpha6beta4 expression. To determine the role of
integrin alpha6beta4 in these
PTHrP-mediated effects, we utilized two strategies to modulate expression of the alpha6 and beta4 subunits in parental and
PTHrP-overexpressing MDA-MB-231 and MCF-7 cells: overexpression of alpha6beta4 by transfection with constructs encoding the alpha6 and beta4 subunits, and suppression of endogenous alpha6beta4 expression by transfection with siRNAs targeting these subunits. We now show that the effects of
PTHrP are mediated via upregulation of
integrin alpha6beta4 expression. We also show that
integrin alpha6beta4 expression is modulated at the
mRNA level, indicating a transcriptional and/or post-transcriptional mechanism of action for
PTHrP.
PTHrP expression also increased the levels of phosphorylated Akt, with a consequent increase in the levels of phosphorylated (inactive)
glycogen synthase kinase-3 (GSK-3). The role of
PTHrP in
breast cancer growth and
metastasis may thus be mediated via upregulation of
integrin alpha6beta4 expression and Akt activation, with consequent inactivation of
GSK-3.