Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism

IGF-II, produced by breast cancer epithelial and stromal cells, enhances tu mor growth by activating the IGF-I receptor (IGF-I-R) via autocrine and par acrine mechanisms. Previously we found that the insulin receptor (IR), whic h is related to the IGF-I-R, is overexpressed in breast cancer cells. Herei n, we find that, in breast cancer the IR is activated by IGF-II, In eight h uman breast cancer cell lines studied there,vas high affinity ICF-II bindin g to the IR, with subsequent IR activation, In these lints, IGF-II had a po tency up to 63% that of insulin. In contrast, in non malignant human breast cells, IGF-II was less than 1% potent as insulin. Via activation of the IR tyrosine kinase IGF-II stimulated breast cancer cell growth. However, IGF- II also activated the IR in breast cancer tissue specimens; IGF-II was 10-1 00% as potent as insulin. The IR occurs in two isoforms generated by altern ative splicing of exon 11; these isoforms are IR-A (Ex11-) and IR-B (Ex11+) . IR-A was predominantly expressed in breast cancer cells and specimens and the potency of IGF-II was correlated to the expression of this isoform (P< 0.0001). These data indicate, therefore, that the IR-A, which binds IGF-II with high affinity, is predominantly expressed in breast cancer cells and r epresents a new autocrine/paracrine loop involved in tumor biology.