Oestrogen/insulin-like growth factor-I receptor interaction in early breast cancer: clinical implications

The expression of oestrogen receptor (ER) and that of the insulin-like growth factor-I receptor (IGF-IR) are positively correlated in breast cancer specimens. Their function is strongly linked in enhancing proliferative activity in normal and malignant human mammary epithelial cells in culture. This review examines the likely role of such a mechanism in the increased breast cancer risk reported in postmenopausal women with abdominal obesity. Precancerous breast lesions show an increased proportion of ER-positive cells with high proliferative activity, and recent studies suggest that genetic mutations or epigenetic variants in the ER alpha gene may increase the ER's sensitivity to oestrogen stimulation. Abdominal obesity in women is associated with higher concentrations both of free oestradiol and free IGF-I. Activation of their respective receptors may induce synergistic stimulation of mammary carcinogenesis. However, there is clinical evidence that progression in precancerous breast lesions may be delayed or reversed. Involution occurs spontaneously in a proportion of duct carcinoma in situ (DCIS) (intraductal) lesions as women approach the menopause, and antioestrogen therapy has been shown to reduce recurrence and progression of DCIS lesions.

Intervention trials in breast cancer prevention would greatly benefit from surrogate response markers which could predict long-term benefit. Changes in ER and IGF-IR expression apart from those in standardised cytomorphological criteria, might predict the likelihood of DCIS involution in cancer prevention trials. Future studies could involve examination of serial core biopsies from normal breast tissue during trials of antioestrogens, retinoids or weight-reduction interventions. Correlation of changes in these markers with changes in circulating IGF-I and oestradiol concentrations may help to clarify the roles of the markers.