Graduation Year

2008

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Cancer Biology

Major Professor

Saïd M Sebti, Ph.D.

Keywords

MAP kinase, Protein kinase A, cAMP, Rho, Tumor suppression

Abstract

Receptor tyrosine kinases such as ErbB2 contribute greatly to human malignant transformation, but the role that other receptors such as ß2 adrenergic receptor (B2 AR)play in cancer is ill defined. Furthermore, while some GTPases such as Ras and RhoA promote oncogenesis, RhoB has been suggested to have tumor suppressive activity. In this thesis the tumor suppressive activity of ß2 adrenergic receptors through blockade of the Ras/Raf/Mek/Erk pathway is demonstrated. Furthermore, this thesis provides strong evidence in support of a tumor suppressive activity of RhoB, but not RhoA, in delaying EbB2 mammary oncogenesis in a transgenic mouse model. Chapter 1 describes a chemical biology approach that identifies a beta 2 adrenergic receptor agonist, ARA-211 (also known as pirbuterol) that suppresses the growth of cultured cells and of human tumors grown in nude mice by a mechanism involving stimulation of the ß2 AR, cAMP production and activation of PKA, which in turn leads to the inactivation of C-Raf, Mek1/2 and Erk1/2. Chapter 2 describes the translation of these findings by ex-vivo treatment of fresh human tumor biopsies, with the ultimate goal of validating this novel therapeutic approach. Chapter 3 describes the generation of transgenic mice that over express ErbB2 along with either RhoB or RhoA to determine the effects of these two small GTPases on ErbB2-mediated mammary tumorigenesis. The findings indicate that overexpression of RhoB, but not RhoA, results in decreased multiplicity and delay in the tumor onset mediated by ErbB2 overexpression.In summary, this thesis work resulted in the discovery of how crosstalk between the ß2 AR/cAMP/PKA circuit with the Raf/Mek/Erk1/2 cascade leads to tumor suppression; and the discovery of the suppression of ErbB2-mediated breast cancer by the GTPase RhoB.

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