Mm. Hijazi et al., Heregulin regulates the actin cytoskeleton and promotes invasive properties in breast cancer cell lines, INT J ONCOL, 17(4), 2000, pp. 629-641
The metastatic process requires changes in tumor cell adhesion properties,
cell motility and remodeling of the extracellular matrix. The erbB(2) proto
-oncogene is overexpressed in approximately 30% of breast cancers and is a
major prognostic parameter when present, in invasive disease. A ligand for
the erbB(2) receptor has not yet been identified but it can be activated by
heterodimerization with heregulin (HRG)-stimulated erbB(3) and erbB(4) rec
eptors. The HRGs are a family of polypeptide growth factors that have been
shown to play a role in embryogenesis, tumor formation, growth and differen
tiation of breast cancer cells. The erbB(3) and erbB(4) receptors are invol
ved in transregulation of erbB(2) signaling. The work presented here sugges
ts biological roles for HRG including regulation of the actin cytoskeleton
and induction of motility and invasion in breast cancer cells. HRG-expressi
ng breast cancer cell lines are characterized by low erbB receptor levels a
nd a high invasive and metastatic index, while those which overexpress erbB
(2) demonstrate minimal invasive potential in vitro and are non-tumorigenic
in vivo. Treatment of the highly tumorigenic and metastatic HRG-expressing
breast cancer cell line MDA-MB-231 with an HRG-neutralizing antibody signi
ficantly inhibited proliferation in culture and motility in the Boyden cham
ber assay. Addition of exogenous HRG to non-invasive erbB(2) overexpressing
cells (SKBr-3) at low concentrations induced formation of pseudopodia, enh
anced phagocytic activity and increased chemomigration and invasion in the
Boyden chamber assay. The specificity of the chemomigration response to HRG
is demonstrated by inhibition with the anti-HRG neutralizing antibody. The
se results suggest that either HRG can act as an autocrine or paracrine lig
and to promote the invasive behavior of breast cancer cells ill vitro or th
us may enhance the metastatic process in vivo.