IGF-IR Signaling in Breast Cancer
Annual rept. 15 Aug 96-14 Aug 97
THOMAS JEFFERSON UNIV PHILADELPHIA PA JEFFERSON CANCER INST
Pagination or Media Count:
Experimental and clinical evidence suggests that the insulin-like growth factor IGF system is involved in the growth of breast cancer cells in vitro and may be important in breast cancer etiology and progression. The IGF-IR is overexpressed in breast cancer cells compared with its levels in normal breast epithelium, and high levels of IGF-IR, or its major substrate IRS-1, correlate with tumor recurrence. Paradoxically, high levels of IGF-IR are associated with better prognosis. Thus, the mechanisms by which abnormal activation of the IGF-IR regulates breast tumor development and progression are not clear. We have developed an in vitro model to investigate the role of the IGF-IR and its different signaling pathways in the emergence of such tumor characteristics as estrogen independence, enhanced autonomous growth, altered motility and cell-cell connections, all of which are determinants of tumor progression. Using cell lines expressing different levels of the IGF-IR, or cells with down-regulated expression of IGF-IR signaling molecules, we demonstrated that overexpressed IGF-IRs promote cell survival in three-dimensional culture by enhancing E-cadherin mediated intercellular adhesion. The IRS-1 signaling pathway is critical for cell survival and resistance to antiestrogens.
- Medicine and Medical Research