Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells
M. Bartucci et al., Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells, CANCER RES, 61(18), 2001, pp. 6747-6754
The insulin-like growth factor I receptor (IGF-JR) is a ubiquitous and mult
ifunctional tyrosine kinase that has been implicated in breast cancer devel
opment. In estrogen receptor (ER)-positive breast tumors, the levels of the
IGF-IR and its substrate, insulin-receptor substrate I (IRS-1), are often
elevated, and these characteristics have been linked with increased radiore
sistance and cancer recurrence. lit vitro, activation of the lGF-IR/ IRS-1
pathway in ER-positive cells improves growth and counteracts apoptosis indu
ced by anticancer treatments. The function of the IGF-IR in hormone-indepen
dent breast cancer is not clear. ER-negative breast cancer cells often expr
ess low levels of the IGF-IR and fail to respond to IGF-I with mitogenesis.
On the other hand, anti-IGF-IR strategies effectively reduced metastatic p
otential of different ER-negative cell lines, suggesting a role of this rec
eptor in late stages of the disease. Here we examined IGF-IR signaling and
function in ER-negative MDA-MB-231 breast cancer cells and their IGF-IR-ove
rexpressing derivatives. We demonstrated that IGF-1 acts as a chemoattracta
nt for these cells. The extent of IGF-1-induced migration reflected IGF-IR
levels and required the activation of phosphatidylinositol 3-kinase (PI-3K)
and p38 kinases. The same pathways promoted IGF-1-dependent motility in ER
positive MCF-7 cells. In contrast with the positive effects on cell migrati
on, IGF-I was unable to stimulate growth or improve survival in MDAMB-231 c
ells, whereas it induced mitogenic and antiapoptotic effects in MCF-7 cells
. Moreover, IGF-I partially restored growth in ER-positive cells treated wi
th PI-3K and ERKI/ERK2 inhibitors, whereas it had no protective effects in
ER-negative cells. The impaired IGF-I growth response of ER-negative cells
was not caused by a low IGF-IR expression, defective IGF-IR tyrosine phosph
orylation, or improper tyrosine phosphorylation of IRS-1. Also, the acute (
15-min) IGF-I activation of PI-3 and Akt kinases was similar in ER-negative
and ER-positive cells. However, a chronic (2-day) IGF-I exposure induced t
he PI-3K/Akt pathway only in MCF-7 cells. The reactivation of this pathway
in ER-negative cells by overexpression of constitutively active Akt mutants
was not sufficient to significantly improve proliferation or survival (wit
h or without IGF-1), which indicated that other pathways are also required
to support these functions. Our results suggest that in breast cancer cells
, IGF-IR can control nonmitogenic processes regardless of the ER status, wh
ereas IGF-IR growth-related functions may depend on ER expression.