Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression.

Abstract

It has been proposed that the insulin-like growth factors (IGFs) can act as autocrine and/or paracrine growth promoters in breast cancer. To investigate this hypothesis, we infected early passage MCF-7 cells with a retroviral vector containing the coding sequence for the IGF-II preprohormone along with a constitutive cytomegalovirus promoter sequence. These cells do not normally express IGF-I or IGF-II. After infection with the retroviral vector, several single cell clones were analyzed. Seven of nine isolated clones expressed very high levels of IGF-II mRNA. Biologically active IGF-II protein was easily detectable in the medium conditioned by the IGF-II-expressing clones, and IGF receptors were down-regulated in these. All IGF-II-expressing clones showed marked morphological changes in anchorage-dependent culture, growing in large clumps and as free-floating colonies. The cells also cloned in soft agar in the absence of estrogen, while the wild-type MCF-7 cells and control cells infected with an irrelevant DNA sequence showed none of these properties. alpha IR-3, an antibody that blocks the type I IGF receptor, inhibited the growth of IGF-II-expressing clones in serum-free medium. This model demonstrates that IGF-II can serve as an autocrine growth stimulant in breast cancer epithelial cells and that IGF-II overexpression may be capable of mediating malignant progression in human breast cancer.

Identification of IGFBP-6 as a significantly downregulated gene by β-catenin in desmoid tumors

“…To show that IGF-II actions were mediated by the IGF-I receptor, IGF-II was coincubated with a monoclonal antibody blocking the IGF-I receptor (aIR-3), which blocks the action as well as binding of IGFs to the IGF-I receptor (Cullen et al, 1992). At 1 mg/ml, aIR-3 almost completely abolished IGF-II-stimulated proliferation.…”

Expression of keratinocyte growth factor and its receptor in human breast cancer

“…Insulin-like growth factor II expression is increased in fibroblasts surrounding breast tumours and is able to stimulate the growth of breast cancer cells, making it a possible candidate as a paracrine growth factor affecting breast cancer progression. However, other growth factors such as KGF may also be involved (Singer et al, 1995;Cullen et al, 1992).…”

The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer

“…An interesting question is whether constitutive overexpression of such proteins might lead to steroid autonomy, generally regarded as an early step in the development of anti-estrogen resistance. In this context it is worth noting that overexpression of IGF-II or IRS-1 in MCF-7 cells leads to decreased estrogen sensitivity (Daly et al, 1991;Cullen et al, 1992;Surmacz and Burgaud, 1995). Interestingly, in a study of 200 node negative breast cancer patients, high expression of IRS-1 correlated with ER positivity and in a subset with small tumors, decreased disease-free survival (Rocha et al, 1997).…”