Several transgenic mice models solidly support the hypothesis that HER2 (ERBB2) overexpression or mutation promotes tumorigenesis. Recently, a HER2 splice variant lacking exon-16 (Δ16HER2) has been detected in human breast carcinomas. This alternative protein, a normal byproduct of HER2, has an increased transforming potency compared to wild-type (wt) HER2 receptors. To examine the ability of Δ16HER2 to transform mammary epithelium in vivo and to monitor Δ16HER2-driven tumorigenesis in live mice, we generated and characterized a mouse line that transgenically expresses both human Δ16HER2 and firefly luciferase under the transcriptional control of the MMTV promoter. All the transgenic females developed multifocal mammary tumors with a rapid onset and an average latency of 15.11 weeks. Immunohistochemical analysis revealed the concurrent expression of luciferase and the human Δ16HER2 oncogene only in the mammary gland and in strict correlation with tumor development. Transgenic Δ16HER2 expressed on the tumor cell plasma membrane from spontaneous mammary adenocarcinomas formed constitutively active homodimers able to activate the oncogenic signal transduction pathway mediated through Src kinase. These new transgenic animals demonstrate the ability of the human Δ16HER2 isoform to transform “per se” mammary epithelium in vivo. The high tumor incidence as well as the short latency strongly suggests that the Δ16HER2 splice variant represents the transforming form of the HER2 oncoprotein.

Kalogris C, Caprodossi S, Amantini C, Lambertucci F, Nabissi M, Morelli M B, Farfariello V, Filosa A, Emiliozzi M C, Mammana G & Santoni G
(2010) Histopathology 57, 744–752
Expression of transient receptor potential vanilloid‐1 (TRPV1) in urothelial cancers of human bladder: relation to clinicopathological and molecular parameters Aims:  To evaluate the expression of transient receptor potential vanilloid type‐1 channel protein (TRPV1) in normal and neoplastic urothelial tissues and to correlate TRPV1 expression with clinicopathological parameters and disease‐specific survival. Methods and results:  TRPV1 expression was analysed in normal and neoplastic urothelial samples at both mRNA and protein levels by quantitative real time polymerase chain reaction (qPCR) and immunohistochemistry, respectively. TRPV1 downregulation was found in urothelial cancer (UC) specimens, which correlated with tumour progression. Moreover, TRPV1 mRNA levels were associated with clinicopathological parameters to assess the role of TRPV1 downregulation as a negative prognostic factor for survival. Kaplan–Meier survival analysis demonstrated a significantly shorter survival in patients showing TRPV1 mRNA downregulation. Multivariate Cox regression analysis indicated further that TRPV1 mRNA expression retained its significance as an independent risk factor. Conclusions:  The progression of UC of human bladder is associated with a marked decrease in TRPV1 expression, with a progressive loss in high‐grade muscle invasive UC. Downregulation of TRPV1 mRNA expression may represent an independent negative prognostic factor for bladder cancer patients.

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