Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes

Abstract

We have assessed ®ve signal transduction pathways to determine the role each might play in the malignant transformation of mammary epithelium initiated by neu, heregulin/NDF, TGFa, v-Ha-ras and c-myc in transgenic mice. The study involves a molecular and pharmacologic assessment of Erk/MAP kinase, Jnk/SAP kinase, PI 3-kinase, protein kinase C, and the Src-related kinases Lck and Fyn. Our results indicate that oncogenes capable of transforming mammary gland epithelium activate and require speci®c signal transduction pathways. For example, mammary tumors initiated by neu, vHa-ras and c-myc have high levels of active Erk/MAP kinase and their anchorage independent growth is strongly inhibited by PD098059, an inhibitor of Mek/ MAP kinase kinase. By contrast, Erk/MAP kinase activity is weak in tumors initiated by TFGa and heregulin/NDF and the corresponding cell lines are not growth inhibited by PD098059. Similarly, PI 3-kinase is strongly activated in neu, TGFa and heregulin/NDF initiated tumor cell lines, but not in c-myc or v-Ha-ras initiated tumor cell lines. The anchorage independent growth of all these tumor cell lines are, however, inhibited by the speci®c PI 3-kinase inhibitor LY294001. Further illustrating this oncogene-based speci®city, PP1, a speci®c inhibitor of the Src-like kinases, Lck and Fyn, blocks anchorage-independent cell growth only in the TGFa initiated mammary tumor cell line. Taken together with additional observations, we conclude that certain oncogenes reliably require the recruitment/activation of speci®c signal transduction pathways. Such speci®c relationships between the initiating oncogene and a required pathway may re¯ect a direct activating e ect or the parallel activation of a pathway that is a necessary oncogenic collaborator for transformation in the mammary gland. The work points to a molecular basis for targeting therapy when an initiating oncogene can be implicated; for example, because of ampli®cation, increased expression, genetic alteration, or heritable characteristics.

Role of Gab2 in mammary tumorigenesis and metastasis

“…Previous studies have shown that in mammary tumor cells transformed by expression of the MMTV-Neu transgene, the PI3K-Akt and the Ras-Erk pathways are profoundly activated (Amundadottir and Leder, 1998;Dankort et al, 2001). We detected very low p-Erk Role of Gab2 in mammary tumorigenesis and metastasis Y Ke et al signals in non-metastatic Gab2 À/À tumor cells with the levels of p-Akt unchanged.…”

“…To identify signaling pathways associated with impaired motility of Gab2-deficient primary tumor cells, we examined the activation status of Erk and Akt, two effectors functioning in different pathways known to be upregulated in mammary carcinogenesis induced by Neu (Amundadottir and Leder, 1998;Dankort et al, 2001). In response to EGF stimulation in vitro, Gab2-deficient tumor cells displayed decreased phospho-Erk (p-Erk) signals, while maintaining a normal level of p-Akt (Figure 6a).…”

Tyrosine Kinase, p56 -induced Cell Motility, and Urokinase-type Plasminogen Activator Secretion Involve Activation of Epidermal Growth Factor Receptor/Extracellular Signal Regulated Kinase Pathways

“…1, E and F, upper panels, lanes 1-8), and the same blots were reprobed with anti-Lck antibody as loading H/R Induces p56 lck and ERK1/2-dependent uPA Secretion 9735 control ( Fig. 1, E and F, lower panels, lanes [1][2][3][4][5][6][7][8]. The inhibitors of EGF receptor have no effect on H/R-induced tyrosine phosphorylation of Lck.…”

“…We and others have recently reported that Lck is expressed in breast cancer tissues and cell lines (5)(6)(7). Lck is a typical Src-like tyrosine kinase, and its activity is regulated by phosphorylation of a highly conserved tyrosine residue, Tyr-505, located near the carboxyl terminus (8).…”

Dual Kinase Inhibition in the Treatment of Breast Cancer: Initial Experience with the EGFR/ErbB-2 Inhibitor Lapatinib

“…Autophosphorylation activates receptor TKs, resulting in activation of signaling pathways involved in cell proliferation, survival, and transformation, including the well-characterized mitogen-activated protein kinase (MAPK) (Erk1/2) and phosphatidylinositol 3′ kinase (PI3K)/AKT pathways ( Fig. 1) [1][2][3]. Overexpression or constitutive activation of the EGFR or ErbB-2 receptors results in cell transformation and is associated with poor clinical outcome in a number of malignancies [4,5].…”