Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis

Abstract

To determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state.

Reversibility and recurrence of IGF-IR-induced mammary tumors

“…This finding suggests that as tumors increase in size, they acquire additional genetic alterations that allow them to become independent of the initiating oncogene, IGF-IR. Regression rates observed with the 500 mm 3 tumors in the MTB-IGF-IR transgenics were similar to those observed in mammary tumors induced by Wnt1 (Gunther et al, 2003) or constitutively active ErbB2 (Moody et al, 2002) but considerably higher than regression rates observed in c-Myc-induced mammary tumors (D'Cruz et al, 2001;Boxer et al, 2004). The effect of tumor size on regression rates was not explored in these other doxycycline inducible mammary tumor models.…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…The rapidity of tumor development in theses mice suggested that activated neu alone might be sufficient to transform mammary epithelium without the need for second site mutations. Conditional expression of neu-NT in the mammary epithelium using a tetracycline regulatory element (MMTV-rTA;TetO-neu-NT) also led to multiple metastatic mammary tumors after administration of doxycycline [151]. Notably, withdrawal of doxycycline led to the regression of both primary mammary tumors and pulmonary metastases, supporting the notion that activated neu alone could promote and sustain mammary tumors.…”

Targeting HER proteins in cancer therapy and the role of the non-target HER3

“…Knockdown of HER2 in HER2-overexpressing cancer cells induces apoptotic cell death (Roh et al, 2000). In mouse models, wherein metastatic mammary carcinomas are induced by the doxycycline induction of Neu overexpression, withdrawal of the Neu oncogene by cessation of doxycycline therapy results in complete regression of the mammary tumours and its associated tumour metastases (Moody et al, 2002). While the simplicity of each of these model systems understates the complexity of HER2-overexpressing human breast cancers, it makes a compelling case that HER2 plays a dominant role in causing and maintaining the transformed phenotype, thus obligating these model systems to oncogenic stimulation.…”