It has become the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide, with rapidly increasing incidence and mortality rates. Breast cancer accounted for 23% (1.38 million) of total new cancer cases and 14% (458,400) of total cancer deaths in 2008 [1]. The incidence rates of breast cancer vary from 19.3 per 100,000 women in Eastern Africa to 89.7 per 100,000 women in Western Europe, while the mortality rate is approximately 6–19 per 100,000 [2]. Tumorigenesis

is a multifactor, multistep complex process that involves click here the cooperation of many genes, in particular the activation of oncogenes and inactivation of tumor suppressor genes. Recent clinical data have emerged demonstrating that Ras family genes play important roles in human tumorigenesis. The activation of Ras proteins by mutational activation or by growth factor stimulation HM781-36B in vivo is a common occurrence in many human cancers and was shown to induce and to be required for tumor growth. The Ras superfamily of small guanosine triphosphatases (GTPases) contains over 150 human members, with the Ras oncogene proteins as the founding members of this family, which is divided into five major branches on the basis of sequence and functional similarities: Ras, Rho, Rab, Ran and Arf. Small GTPases share a common biochemical mechanism. The Ras superfamily of GTPases function as GDP/GTP-regulated molecular

switches. They alternate between GTP- and GDP-bound conformations in which the GTP-bound HMPL-504 research buy conformation represents the “on” state and the GDP-bound conformation represents the “off” state. Upon binding, two regions of Ras undergo dramatic structural changes depending on the type of bound nucleotide [3]. Small GTPases exhibit high-affinity binding for

GDP and GTP and possess low intrinsic GTP hydrolysis and GDP/GTP exchange activities. GDP/GTP cycling is controlled by two main classes of regulatory proteins. Guanine-nucleotide-exchange factors (GEFs) promote the formation of the active, GTP-bound Selleckchem Ribociclib form, whereas GTPase-activating proteins (GAPs) accelerate the intrinsic GTPase activity to promote formation of the inactive, GDP-bound form [4, 5]. GTPases within a branch use shared and distinct GAPs and GEFs. GTPases in different branches exhibit structurally distinct but mechanistically similar GAPs and GEFs. The two nucleotide-bound states have similar conformations but have pronounced differences corresponding to the switch I (Ras residues 30–38) and switch II (59–67) regions; the GTP-bound conformation possesses high affinity for effector targets [6, 7]. It is mainly through the conformational changes in these two switches that the regulatory proteins and effectors modulate the nucleotide status of the small GTPases [8]. Ras-associated binding (Rab)-GTPases are members of the Ras family of small GTPases.