Synergistic Interaction of the Neu Proto-Oncogene Product and Transforming Growth Factor α in the Mammary Epithelium of Transgenic Mice

Abstract

Transgenic mice expressing either the neu proto-oncogene or transforming growth factor (TGF-␣) in the mammary epithelium develop spontaneous focal mammary tumors that occur after a long latency. Since the epidermal growth factor receptor (EGFR) and Neu are capable of forming heterodimers that are responsive to EGFR ligands such as TGF-␣, we examined whether coexpression of TGF-␣ and Neu in mammary epithelium could cooperate to accelerate the onset of mammary tumors. To test this hypothesis, we interbred separate transgenic strains harboring either a mouse mammary tumor virus/TGF-␣ or a mouse mammary tumor virus/neu transgene to generate bitransgenic mice that coexpress TGF-␣ and neu in the mammary epithelium. Female mice coexpressing TGF-␣ and neu developed multifocal mammary tumors which arose after a significantly shorter latency period than either parental strain alone. The development of these mammary tumors was correlated with the tyrosine phosphorylation of Neu and the recruitment of c-Src to the Neu complex. Immunoprecipitation and immunoblot analyses with EGFR-and Neu-specific antisera, however, failed to detect physical complexes of these two receptors. Taken together, these observations suggest that Neu and TGF-␣ cooperate in mammary tumorigenesis through a mechanism involving Neu and EGFR transactivation.

The role of transforming growth factor alpha production and ErbB-2 overexpression in induction of tumorigenicity of lung epithelial cells

“…We hypothesized that the secretion of TGF-at in E6T cells induced constitutive heterodimer formation between EGFR and ErbB-2 and a change in configuration of ErbB-2. with the tumorigenic phenotype as recently demonstrated by Muller et al (1996) in transgenic mice bearing mammary tumours. In addition, neither the number of EGFR-ErbB-2 heterodimers nor their distribution was analysed in our study.…”

“…Studies using transgenic mice suggest that interactions of ErbB-2 and transforming growth factor (TGF)-a may also play a role in induction of tumorigenicity. Transgenic strains expressing an EGFR-specific ligand, TGF-at and wild-type ErbB-2 develop mammary tumours at an accelerated rate (Muller et al, 1996).…”

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

“…TGFa is the most commonly identi®ed EGF-like growth factor in primary breast tumors as evidenced by the presence of TGFa mRNA and/or protein in 30 ± 70% of cases reported (reviewed in Rudland et al, 1995). In addition, overexpression of TGFa in the mammary gland of transgenic mice is potently oncogenic (Sandgren et al, 1990(Sandgren et al, , 1995Jhappan et al, 1990;Matsui et al, 1990;Halter et al, 1992;Smith et al, 1995), and coexpression of TGFa with other oncogenes shortens tumor latency (Sandgren et al, 1995;Amundadottir et al, 1995Amundadottir et al, , 1996Muller et al, 1996;Davies et al, 1999).…”

Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2

“…Despite this, TGFa may exert greater mitogenic potency than EGF in vitro (Gabelman and Emerman, 1992) and in vivo (Gan et al, 1987), suggesting that TGFa functions as an EGFR superagonist' in some cells and tissues. Moreover, unlike EGF, TGFa has been widely implicated in the pathogenesis of autocrine growth loops in cancer cells and tumours (Mellon et al, 1996;Muller et al, 1996;Stromberg et al, 1992). These functional distinctions between EGF and TGFa have led to a search for physical properties explaining their presumably distinct biological roles.…”