Estradiol regulates the insulin-like growth factor-I (IGF-I) signalling pathway: a crucial role of phosphatidylinositol 3-kinase (PI 3-kinase) in estrogens requirement for growth of MCF-7 human breast carcinoma cells.
Estrogens can stimulate the proliferation of estrogen-responsive breast cancer cells by increasing their proliferative response to insulin-like growth factors. With a view to investigating the molecular mechanisms implicated, we studied the effect of estradiol on the expression of proteins implicated in the insulin-like growth factor signalling pathway. Estradiol dose- and time-dependently increased the expression of insulin receptor substrate-1 and the p85/p110 subunits of phosphatidylinositol 3-kinase but did not change those of ERK2 and Akt/PKB. ICI 182,780 did not inhibit estradiol-induced IRS-1 and p85 expression. Moreover, two distinct estradiol-BSA conjugate compounds were as effective as estradiol in inducing IRS-1 and p85/p110 expression indicating the possible implication of an estradiol membrane receptor. Comparative analysis of steroids-depleted and steroids-treated cells showed that IGF-I only stimulates cell growth in the latter condition. Nevertheless, expression of a constitutively active form of PI 3-kinase in steroid-depleted cells triggers proliferation. These results demonstrate that estradiol positively regulates essential proteins of the IGF signalling pathway and put in evidence that phosphatidylinositol 3-kinase plays a central role in the synergistic pro-proliferative action of estradiol and IGF-I.
Bernard
Laurence
L
Institut National de la Santé et de la Recherche Médicale, Unité 515, Croissance, Différenciation et Processus Tumoraux, Hôpital Saint-Antoine, Paris, France.
Legay
Christine
C
Adriaenssens
Eric
E
Mougel
Alexandra
A
Ricort
Jean-Marc
JM
D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage*; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D004967:Estrogens; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases