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Role of IGF1R in breast cancer

There has been great interest in understanding the role of IGFs in breast cancer, and this has led to therapeutic targeting. We developed the first transgenic model of IGF-IR-mediated tumorigenesis (a). We subsequently showed that IGF-IR transforms mammary epithelial cells and causes EMT via a novel pathway involving NF-kB and snail regulation of E-cadherin (a pathway now validated by others) (b). We have focused downstream IGF1R signaling. We provided fundamental insight into the role of insulin receptor substrates (IRSs) in human breast cancer. We initially discovered that IRSs are turned over by the proteasome following IGF activation (c), and that IRSs undergo dramatic hormonal regulation in the mouse mammary gland (d), and. Transgenic overexpression in the mammary gland was sufficient to cause tumorigenesis (e). Genetic knockout of IRSs was found to alter lactation. In human breast cancer (f), IRS levels were found to correlate with tamoxifen resistance in a large (~1,600) cohort of breast cancer patients (g). This is consistent with our studies showing cross-talk between estrogen receptor and IGFs (h-j). Surprisingly, while others have suggested a crosstalk between ErbB2 and IRSs, we didn’t find this using both murine and human cell lines, and mouse models (k). Current work focuses on identification of biomarkers of IGF1R signaling using transcriptomics (l), proteomics (m) and suggests IGF1R inhibitors may be most active in triple negative breast cancer (n) and invasive lobular cancer.

a.            Litzenburger BC, Kim HJ, Kuiatse I, Carboni JM, Attar RM, Gottardis MM, Fairchild CR, Lee AV. BMS-536924 reverses IGF-IR-induced transformation of mammary epithelial cells and causes growth inhibition and polarization of MCF7 cells. Clinical cancer research. 2009 Jan 1;15(1):226-37. PMID: 19118050. PMCID: PMC2819349.

b.            Kim HJ, Litzenburger BC, Cui X, Delgado DA, Grabiner BC, Lin X, Lewis MT, Gottardis MM, Wong TW, Attar RM, Carboni JM, Lee AV. Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail. Molecular and cellular biology. 2007 Apr;27(8):3165-75. PMID: 17296734. PMCID: PMC1899918.

c.             Carboni JM, Lee AV, Hadsell DL, Rowley BR, Lee FY, Bol DK, Camuso AE, Gottardis M, Greer AF, Ho CP, Hurlburt W, Li A, Saulnier M, Velaparthi U, Wang C, Wen ML, Westhouse RA, Wittman M, Zimmermann K, Rupnow BA, Wong TW. Tumor development by transgenic expression of a constitutively active insulin-like growth factor I receptor. Cancer research. 2005 May 1;65(9):3781-7. PMID: 15867374.

d.            Lee AV, Zhang P, Ivanova M, Bonnette S, Oesterreich S, Rosen JM, Grimm S, Hovey RC, Vonderhaar BK, Kahn CR, Torres D, George J, Mohsin S, Allred DC, Hadsell DL. Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland. Endocrinol. 2003;144:2683-94. PMID: 12746333.

e.            Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang X, Divisova J, Britton OL, Mohsin S, Allred DC, Hadsell DL, Lee AV. Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol Cell Biol. 2006;26:9302-14. PMID: 17030631. PMCID: PMC1698542

f.              Hadsell DL, Olea W, Lawrence N, George J, Torres D, Kadowaki T, Lee AV. Decreased lactation capacity and altered milk composition in insulin receptor substrate null mice is associated with decreased maternal body mass and reduced insulin-dependent phosphorylation of mammary Akt. J Endocrinol. 2007 Aug;194(2):327-36

g.            Migliaccio I, Wu MF, Gutierrez C, Malorni L, Mohsin SK, Allred DC, Hilsenbeck SG, Osborne CK, Weiss H, Lee AV. Nuclear IRS-1 predicts tamoxifen response in patients with early breast cancer. Breast cancer research and treatment. 2010;123:651-60. PMID: 19924529. PMCID: PMC2891842.

h.            Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D. Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol. 1999 May;13(5):787-96. PMID: 10319328    

i.              Casa AJ, Potter AS, Malik S, Lazard Z, Kuiatse I, Kim HT, Tsimelzon A, Creighton CJ, Hilsenbeck SG, Brown PH, Oesterreich S, Lee AV. Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth. Breast Cancer Research and Treatment. 2012 Feb;132(1):61-73. PMID: 21541704. PMCID: 3936881.

j.              Potter AS, Casa AJ, Lee AV. J Cell Biochem. 2012 Jan;113(1):110-21.Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity. PMID: 21882221

k.             Farabaugh SM, Chan BT, Cui X, Dearth RK, Lee AV. Lack of interaction between ErbB2 and insulin receptor substrate signaling in breast cancer. Cell Commun Signal. 2016 Oct 21;14(1):25. PMID: 27765041; PMCID: PMC5073819

l.              Erdem C, Nagle AM, Casa AJ, Litzenburger BC, Wang YF, Taylor DL, Lee AV*, Lezon TR*. Proteomic screening and lasso regression reveal differential signaling in insulin and insulin-like growth factor I pathways. Mol Cell Proteomics. 2016 Jun 30 PMID: 27364358

m.           Creighton CJ, Casa A, Lazard Z, Huang S, Tsimelzon A, Hilsenbeck SG, Osborne CK, Lee AV. Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol. 2008 Sep 1;26(25):4078-85. PMID: 18757322. PMCID: 2654368.

n.            Litzenburger BC, Creighton CJ, Tsimelzon A, Chan BT, Hilsenbeck SG, Wang T, Carboni JM, Gottardis MM, Huang F, Chang JC, Lewis MT, Rimawi MF, Lee AV. High IGF-IR activity in triple-negative breast cancer cell lines and tumorgrafts correlates with sensitivity to anti-IGF-IR therapy. Clin Cancer Res. 2011 Apr 15;17(8):2314-27. PMCID: 3926653.