Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors.

Abstract

Amplification of the Neu/c-erbB-2 receptor tyrosine kinase has been implicated as an important event in the genesis of human breast cancer. Indeed, transgenic mice bearing either an activated form of neu or the wild-type proto-oncogene under the transcriptional control of the mouse mammary tumor virus promoterenhancer frequently develop mammary carcinomas (L. Bouchard, L. Lamarre, P. J. Tremblay, and P. Jolicoeur, Cell 57:931-936, 1989 Leder, Cell 54:105-115, 1988). Induction of mammary tumors in transgenic mice expressing the wild-type Neu receptor is associated with activation of the receptor's intrinsic tyrosine kinase activity (Guy et al., Proc. Natl. Acad. Sci. USA 89:10578-10582, 1992). Here, we demonstrate that activation of Neu in these transgenic mice occurs through somatic mutations located within the transgene itself. Sequence analyses of these mutations revealed that they contain in-frame deletions of 7 to 12 amino acids in the extracellular region proximal to the transmembrane domain. Introduction of these mutations into a wild-type neu cDNA results in an increased transforming ability of the altered Neu tyrosine kinase. These observations suggest that oncogenic activation of Neu in mammary tumorigenesis frequently occurs by somatic mutation.The neu (c-erbB-2 or HER2) proto-oncogene encodes a receptor tyrosine kinase belonging to the epidermal growth factor receptor family (2, 9). Oncogenic activation of Neu can occur through multiple molecular mechanisms, including a point mutation in its transmembrane domain (3) and deletion of the extracellular domain (4). Amplification and consequent overexpression of neulc-erbB-2 have also been observed in a significant proportion of human breast and ovarian cancers (14,24,27). In fact, several studies have shown that the degree of amplification is inversely correlated to a poor clinical outcome for breast cancer patients in whom the cancer has not spread to the lymph nodes (11,22). Although elevated levels of neulc-erbB-2 are observed in these human cancers, no comparable mutations have been detected in these tumor samples (15).Consistent with these clinical observations, expression of activated or wild-type neu targeted to the mammary epithelia of transgenic mice results in the efficient induction of mammary tumors (5,12,19). In mice expressing elevated levels of the wild-type Neu protein, the appearance of mammary tumors is associated with a high incidence of metastatic disease (12). Mammary gland-specific expression of Neu results in the appearance of focal mammary tumors after a variable latency period (12). Both the focal nature and long latency period suggest that additional genetic events are needed to transform the mammary epithelium. Mammary tumorigenesis in these transgenic strains is correlated with elevated intrinsic Neu tyrosine kinase activity and the de novo tyrosine phosphorylation of several cellular proteins (12). The RNA and protein (12).While it is clear that activation of Neu plays an important role in the induction of mammary tumors...

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer

“…The N202 model harbors the rat Neu proto-oncogene under the transcriptional control of the mouse mammary tumor virus promoter in the FVB/N inbred mouse strain. During tumorigenesis, deletions occur in sequences encoding the juxta-membrane region of Neu resulting in the constitutive activation of its tyrosine kinase activity (Siegel et al, 1994;Siegel and Muller, 1996). Table 1 illustrates that several Notch-related genes were overexpressed in tumorspheres compared with mammospheres.…”

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

“…Gene amplification and overexpression of Neu/ErbB-2, a member of the epidermal growth factor receptor tyrosine kinase family, is found in 25-30% of primary breast cancer patients, who display a trend of early stage metastasis and poor survival rate (Slamon et al, 1987). These clinical observations have been clearly supported by the establishment of several Neu/ErbB-2-dependent transgenic models of breast cancer, showing a causal relationship between overexpression of Neu/ErbB-2 and the development of metastatic breast tumors (Muller et al, 1988;Siegel et al, 1994;Ursini-Siegel et al, 2007). In addition, it is becoming clear that Neu/ErbB-2-induced signaling pathways can be influenced by other signaling pathways leading to breast tumorigenesis.…”

Formation of Neu/ErbB2-induced mammary tumors is unaffected by loss of ErbB4

“…The longer latency period of tumors induced by wild-type MMTV-Neu is caused by the requirement for additional genetic events to enable tumor formation. These tumors generally harbor somatic mutations that constitutively activate ErbB2 by promoting inter-receptor disulfide bond formation (Siegel et al, 1994). Tumorigenesis induced by MMTV-Neu can also be accelerated through cooperation with other genetic lesions, including overexpression of TGF-a or a dominant active form of p53 (Muller et al, 1996;Li et al, 1997).…”