Activation of the transmembrane tyrosine kinase insulin-like growth factor 1 receptor (IGF-1R) contributes to breast cancer progression. Nonetheless, the mechanisms by which the IGF-1R contributes to breast cancer progression need to be better characterized to further develop therapeutic strategies that target this pathway. It is known that cytochrome P450 monooxygenases synthesize metabolites from endogenous and exogenous sources that promote breast cancer proliferation. Here we propose that activity of the IGF-1R modulates the activity of CYP1A1 to promote breast cancer cell proliferation. We have found that IGF-IR activation by treatment with IGF1 (5nM ) for 4hrs induces cytochrome P450 1A1 (CYP1A1) mRNA levels in estrogen receptor (ER) positive line T47D-CO, but not ER negative line MDA-MB-231. Treatment with IGF1 promotes the proliferation of ER positive lines T47D-CO and MCF7. Interestingly, we found that treatment with IGF1 only partially compensates the growth-inhibition induced by CYP1A1 knock down by siRNA, suggesting that IGF1 requires CYP1A1 for full promotion of cell growth. These preliminary data suggest that IGF-1 signaling functions, in part, through CYP1A1 to promote ER positive breast cancer cell proliferation. The mechanism of IGF-1 signaling through CYP1A1 is novel and may represent an effector mechanism for IGF-1. Further understanding the role of CYP1A1 downstream of the IGF-1R may allow novel approaches for inhibition of breast cancer cell proliferation downstream of the IGF-1R.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-11.