Breast cancer resistance to anti-estrogens may be caused by cross-talk between growth factor receptor signaling and estrogenic pathways. Our recent data suggest that the enzymatic activity of aromatase can be increased by AKT, a kinase activated by several growth factor receptor tyrosine kinase signaling cascades (e.g., HER2/Neu). Aromatase is the rate-limiting enzyme complex involved in the biosynthesis of estrogens, which exert mitogenic, anti-apoptotic, and growth-stimulatory effects in mammary tissues. Therefore, growth factor receptor signaling may moderate aromatase activity, estrogen production, and the consequent activation of estrogen-responsive pathways.
Aim 1 - To determine if AKT phosphorylates aromatase to increase its enzymatic activity in vitro.
Aim 2 - To determine whether active AKT modulates aromatase activity in vivo and aromatase-induced morphological alterations in the mammary gland of transgenic mice.
Aim 3 - To determine whether over-expression of active AKT or HER2/Neu in the mammary epithelium of transgenic mice confers resistance to aromatase inhibitors.
Aim 1 will utilize molecular techniques and cell lines to determine the ability of AKT to phosphoregulate aromatase in vitro.
Aims 2 and 3 will use histomorphological, immunohistochemical, and molecular analyses of transgenic mouse models to determine whether active AKT and HER2/Neu can modulate aromatase activity in vivo, and whether these oncogenes confer resistance to aromatase inhibitors. Results from these studies may provide novel drug targets for hormone-dependent cancers while furthering our understanding of the communication between growth factor receptor signaling and estrogenic pathways. Relevance: Aromatase inhibitors are used clinically to decrease the aromatase-mediated production of estrogens for the treatment of estrogen-dependent breast cancers. While aromatase inhibitors are initially very effective, tumors typically exhibit initial or acquired drug resistance, necessitating the development of further therapeutics. Our work will investigate potential mechanisms by which cancer cells mediate escape from aromatase inhibitor therapy to provide new drug targets for the treatment of breast cancer. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA121900-02
Application #
7425050
Study Section
Special Emphasis Panel (ZRG1-F09-K (20))
Program Officer
Jakowlew, Sonia B
Project Start
2007-04-11
Project End
2009-04-10
Budget Start
2008-04-11
Budget End
2009-04-10
Support Year
2
Fiscal Year
2008
Total Cost
$51,278
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Sangai, Takafumi; Akcakanat, Argun; Chen, Huiqin et al. (2012) Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res 18:5816-28
Balko, Justin M; Miller, Todd W; Morrison, Meghan M et al. (2012) The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium. Proc Natl Acad Sci U S A 109:221-6
Miller, Todd W; Balko, Justin M; Fox, Emily M et al. (2011) ER?-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 1:338-51
Fox, Emily M; Miller, Todd W; Balko, Justin M et al. (2011) A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Res 71:6773-84
Miller, Todd W; Balko, Justin M; Ghazoui, Zara et al. (2011) A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance. Clin Cancer Res 17:2024-34
Miller, Todd W; Hennessy, Bryan T; González-Angulo, Ana M et al. (2010) Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 120:2406-13
Shah, Chirayu; Miller, Todd W; Wyatt, Shelby K et al. (2009) Imaging biomarkers predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer. Clin Cancer Res 15:4712-21
Miller, Todd W; Pérez-Torres, Marianela; Narasanna, Archana et al. (2009) Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 69:4192-201
Miller, Todd W; Forbes, James T; Shah, Chirayu et al. (2009) Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res 15:7266-76
Miller, Todd W; Shin, Incheol; Kagawa, Norio et al. (2008) Aromatase is phosphorylated in situ at serine-118. J Steroid Biochem Mol Biol 112:95-101