Elucidating molecular mechanisms of ErbB2/Neu-induced mammary tumorigenesis.

摘要

The 15-30% of human breast cancers that have upregulated HER2/ErbB2/Neu are highly aggressive and resistant to traditional treatments, resulting in poor prognosis. To identify novel therapeutic targets, we derived the transcriptomes associated with tumor progression in two independent mouse models of ErbB2/Neu-induced tumorigenesis. From MMTV-Neu mice, we identified 324 candidate genes unique to ErbB2/Neu-induced tumors relative to wild-type mammary glands. A subset of these genes also changed expression levels in preneoplastic mammary glands, indicating a pivotal role early in ErbB2/Neu-initiated tumorigenesis.; Downregulation of several known transforming growth factor (TGF)-beta target genes in the ErbB2/Neu molecular signature suggested attenuation of the TGF-beta signaling cascade in these tumors. Analysis of TGF-beta-Receptor-I/ALK5 by western blot and immunohistochemistry confirmed that Smad-dependent TGF-beta signaling was inactive in these tumors. Although absent in most of the tumor, colocalization of phosphorylated Smad2 and Activin-Receptor-IB/ALK4 at the tumor periphery suggested functional Activin signaling at the leading edge of these tumors. Collectively, these data indicate intrinsic TGF-beta pathway suppression in ErbB2/Neu tumors via loss of TGF-beta-Receptor-I/ALK5.; Recent studies have shown that pregnancy can accelerate ErbB2/Neu tumor development, inducing a susceptible cell population in MMTV-Neu mammary glands. The stochastic pattern of tumor development in multiparous MMTV-Neu mice suggests additional events are required for ErbB2/Neu oncogenesis. It remains unclear whether such events are genetic or reflective of the dynamic, pregnancy-associated hormonal control of the gland. Bitransgenic mice generated by breeding MMTV-Neu mice with a model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells targeted by ErbB2/Neu for transformation. (Abstract shortened by UMI.)