Insulin receptor substrates 1 and 2 (IRSs) are large adaptor proteins downstream of insulin-like growth factor-I receptor (IGF-IR) which modulate normal growth, metabolism, survival, and differentiation. Recent studies have shown that IRSs can interact with, and are functionally required for the transforming ability of many oncogenes, and IRSs are elevated and hyperactive in many human tumors including breast cancer. The long-term goal of these studies is to understand the role of inuslin receptor substrates (IRSs) in breast cancer, and determine if they may have a role in predicting response to anti-IGF-IR inhibitors. To better understand the role of IRSs in mammary gland development and breast cancer, in the last funding period, we created and studied several novel in vitro and in vivo models of IRS action. Using IRS-null mice we found that IRSs are required for embryonic mammary bud formation and for maximal lactation. Using human immortalized MCF-10A cells we showed that overexpression of IRSs disrupted formation of acini by altering polarity, proliferation, and survival. Finally, we generated transgenic mice with mammary-specific overexpression of either IRS-1 or IRS-2 with both lines of mice displaying progressive mammary hyperplasia, tumors, and metastasis. Intriguingly, studies from others using IRS-2-null mice have shown that only IRS-2 is required for mammary tumor metastasis. These studies have raised three fundamental questions: 1) How do IRSs modulate mammary cell polarity, transformation, and tumorigenesis? 2) Why do both IRS-1 and IRS-2 cause transformation, but only IRS-2 is required for metastasis? 3) Are IRSs important in breast cancer progression and prognosis, and can levels and/or activity predict response to anti-IGF-IR inhibitors? We will address these questions with the following specific aims: 1) Do both IRS-1 and IRS-2 disrupt morphogenesis of MCF-10A acini via aPKC mediated disruption of the polarity complex, and promote proliferation and survival downstream of IGF-IR? 2) Does IRS-2 utilize a unique bi-directional positive regulation of NF-?B activity to modulate migration, invasion, and metastasis? 3) Are IRSs important in breast cancer progression and prognosis, and can they be used as predictors of response to anti-IGF-IR therapy? The long-term impact of these studies will be a better understanidng of IRS action in breast cancer, and a possible new biomarker for predicting response to IGF-IR inhibitors in breast cancer.

Public Health Relevance

The goal of this study is to better understand the role of signaling adaptors (IRSs) in breast cancer. The study will elucidate IRS function, and then translate this into human breast cancer to test if they affect patient prognosis and predict response to anti-IGF-IR inhibitors.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA094118-10
Application #
8624531
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Hildesheim, Jeffrey
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Fu, Xiaoyong; Creighton, Chad J; Biswal, Nrusingh C et al. (2014) Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase. Breast Cancer Res 16:430
Pathiraja, Thushangi N; Nayak, Shweta R; Xi, Yuanxin et al. (2014) Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer. Sci Transl Med 6:229ra41
Lee, Adrian V; Davidson, Nancy E (2014) Breast cancer in 2013: Genomics, drug approval, and optimal treatment duration. Nat Rev Clin Oncol 11:71-2
Boone, David N; Lee, Adrian V (2012) Targeting the insulin-like growth factor receptor: developing biomarkers from gene expression profiling. Crit Rev Oncog 17:161-73
Potter, Adam S; Casa, Angelo J; Lee, Adrian V (2012) Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity. J Cell Biochem 113:110-21
Litzenburger, Beate C; Creighton, Chad J; Tsimelzon, Anna et al. (2011) High IGF-IR activity in triple-negative breast cancer cell lines and tumorgrafts correlates with sensitivity to anti-IGF-IR therapy. Clin Cancer Res 17:2314-27
Wang, Jinhua; Kuiatse, Isere; Lee, Adrian V et al. (2010) Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation. Mol Cancer Res 8:266-77
Litzenburger, Beate C; Kim, Hyun-Jung; Kuiatse, Isere et al. (2009) BMS-536924 reverses IGF-IR-induced transformation of mammary epithelial cells and causes growth inhibition and polarization of MCF7 cells. Clin Cancer Res 15:226-37
Chan, Bonita Tak-Yee; Lee, Adrian V (2008) Insulin receptor substrates (IRSs) and breast tumorigenesis. J Mammary Gland Biol Neoplasia 13:415-22
Heckman, Brandy M; Chakravarty, Geetika; Vargo-Gogola, Tracy et al. (2007) Crosstalk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development. Dev Biol 309:137-49

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