In the initial stages of prostate cancer, growth of the tumor is sensitive to androgen ablation therapy. However, in many cases, the tumor progresses to an androgen-independent state for which there is no known therapy. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (RTK) has often been implicated in the development of the androgen-independent phenotype. While HER1 and HER2 have been widely studied in prostate cancer, the role of HER3 is relatively unknown. In this application we propose to investigate the role of HER3 in the development of an androgen-independent phenotype. Preliminary data show that androgen independent prostate tumor cell lines overexpress HER3 and show increased activation of Akt compared to androgen-dependent cells. In addition, we made the novel observation that androgen independent cell lines expressed greater levels of HER1/HER3 heterodimers compared to androgen dependent cells. Overexpression of HER3 in an androgen dependent cell line induced increased proliferation and androgen-independence. We hypothesize that overexpression of HER3 in prostate cancer induces the formation of HER1/HER3 heterodimers, which results in androgen independence mediated by Akt. Based on this hypothesis, we propose the following: ? Aim 1. To determine if androgen-independence is a result of HER3 overexpression. We will investigate whether HER3 regulates androgen-dependence and induces androgen receptor transactivation. Also, in a retrospective immunohistochemical study using paraffin-embedded tissues we will examine whether HER3 expression correlates with increased proliferation and a poor clinical outcome in human prostate tumors. ? Aim 2. To elucidate the role of HER3 overexpression in the induction of the androgen-independent phenotype. We will evaluate the contribution of HER3 overexpression to increased Akt phosphorylation and investigate the role of HER1/HER3 heterodimerization in HER3-induced androgen independence. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA109057-02
Application #
7120118
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2005-09-07
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$105,814
Indirect Cost
Name
University of California Davis
Department
Urology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Jathal, Maitreyee K; Chen, Liqun; Mudryj, Maria et al. (2011) Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block. Immunol Endocr Metab Agents Med Chem 11:131-149
Chen, Liqun; Mooso, Benjamin A; Jathal, Maitreyee K et al. (2011) Dual EGFR/HER2 inhibition sensitizes prostate cancer cells to androgen withdrawal by suppressing ErbB3. Clin Cancer Res 17:6218-28
Chen, Liqun; Siddiqui, Salma; Bose, Swagata et al. (2010) Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells. Cancer Res 70:5994-6003
Bedolla, Roble G; Wang, Yu; Asuncion, Alfredo et al. (2009) Nuclear versus cytoplasmic localization of filamin A in prostate cancer: immunohistochemical correlation with metastases. Clin Cancer Res 15:788-96
Wang, Y; Mikhailova, M; Bose, S et al. (2008) Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. Oncogene 27:7106-17
Mikhailova, Margarita; Wang, Yu; Bedolla, Roble et al. (2008) AKT regulates androgen receptor-dependent growth and PSA expression in prostate cancer. Adv Exp Med Biol 617:397-405
Wang, Y; Kreisberg, J I; Bedolla, R G et al. (2007) A 90 kDa fragment of filamin A promotes Casodex-induced growth inhibition in Casodex-resistant androgen receptor positive C4-2 prostate cancer cells. Oncogene 26:6061-70
Bedolla, Roble; Prihoda, Thomas J; Kreisberg, Jeffrey I et al. (2007) Determining risk of biochemical recurrence in prostate cancer by immunohistochemical detection of PTEN expression and Akt activation. Clin Cancer Res 13:3860-7