Insulin-like growth factor-l (IGF-I) signaling has been implicated in the pathogenesis of breast and other cancers. The IGF-I receptor (IGF-IR) activates pathways that regulate key processes associated with tumorigenesis- hyperproliferation, enhanced survival and migration. Using an in vitro 3-D breast epithelial model to investigate IGF-IR pathways that specifically regulate these processes, I observed that IGF-I hyper-stimulation leads to formation of hyperproliferative structures with filled lumen; these structures resemble carcinoma-in-situ. Using this model, I uncovered novel activities of Akt and other signaling proteins involved in IGF-I stimulated effects on survival, migration and invasion and I plan to investigate the underlying mechanisms.
In Specific Aim 1, I will investigate mechanisms responsible for regulation of migration and invasion by IGF-I. Akt1 was observed to suppress IGF-I- and EGF-stimulated migration whereas Akt2 is required for migration. Studies to elucidate the underlying basis for these contrasting, isoform-specific functions and to identify isoform-specific targets of Akt will be performed.
In Specific Aim 2, I will examine the cellular pathways that regulate cell survival and filling of the lumen by IGF-I. While Akt2 was found to be critical for anti-apoptotic activity associated with IGF-l-induced luminal filling, rapamycin-mediated inhibition of mTOR, a downstream target of Akt signaling, does not suppress the anti-apoptotic effects of IGF-I. These results revealed the contribution of rapamycin-insensitive pathway(s) to IGF-I mediated cell survival. Utilizing both candidate-based and screening approaches, this project aims to identify these pathways, as well as other uncharacterized, novel molecules critical for IGF-I mediated cell survival and luminal filing. Targeted therapies, which specifically inhibit molecules activated in tumors, are becoming a common strategy and inhibitors targeting IGF-IR/PI-3K/Akt are in early clinical development. Given the complexity of interactions between signaling networks in tumor cells, a thorough understanding of the functions of these proteins is critical for optimal use of new biological therapies. Strategies to identify novel targets are also critical as tumor cells utilize multiple mechanisms to evade therapeutic inhibition. Hanna Irie is a researcher and a medical oncologist specializing in breast cancer who is committed to becoming an independent laboratory-based scientist dedicated to understanding the role of growth factors in breast tumorigenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA107231-01A2
Application #
7145751
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2006-09-01
Project End
2011-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$135,108
Indirect Cost
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Irie, Hanna Y; Shrestha, Yashaswi; Selfors, Laura M et al. (2010) PTK6 regulates IGF-1-induced anchorage-independent survival. PLoS One 5:e11729