Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer.
The insulin-like growth factor I (IGF-I) receptor (IGF-IR) is a multifunctional transmembrane tyrosine kinase that has been implicated in neoplastic transformation. The tumorigenic potential of IGF-IR relies on its strong anti-apoptotic and mitogenic activity. The growth and survival signals of IGF-IR are mediated through multiple intracellular pathways, many of which emanate from insulin receptor substrate 1 (IRS-1). In hormone-dependent breast cancer cells, IGF-IR and IRS-1 are often co-expressed with the estrogen receptor alpha (ERalpha), and IGF-I and ER systems are engaged in a powerful functional cross-talk. Most notably, activation of ERalpha upregulates the expression of IRS-1, IGF-IR, and IGF-1, which results in amplification of IGF-I responses. Reciprocally, stimulation of IGF-IR increases the phosphorylation and activity of ERalpha. In contrast, in ERalpha-negative breast cancer cells and tumors, the levels of IGF-IR and IRS-1 are often decreased and IGF-I is non-mitogenic. Our data suggest that defective IGF-IR signaling in ERalpha-negative cells is related, at least in part, to improper activation of the IRS-1/PI-3K/Akt/GSK-3 pathway and lack of Rb1 phosphorylation. These defects are partially reversed by re-expression of ERalpha. Interestingly, some non-mitogenic IGF-I responses, such as migration and invasion are retained in the absence of ERalpha, suggesting that IGF-IR function in breast cancer cells might depend on the ERalpha status. The understanding of how ERalpha may dictate IGF-I responses will help in devising rational anti-IGF-IR strategies for breast cancer treatment.
Surmacz
E
E
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. eva.surmacz@jefferson.edu
Bartucci
M
M
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D047628:Estrogen Receptor alpha; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1