Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most
skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving
reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced
skin cancer. Following the induction of benign squamous
papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor
AG825 and
tumor progression monitored.
AG825 treatment reduced
tumor volume, increased
tumor regression, and delayed the development of malignant
squamous cell carcinoma (SCC). Progression to
malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And
Metalloproteinase 12) transcripts and
protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased
ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of
skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or
siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or
siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced
skin cancer. Inhibition of Erbb2/HER2 reduced
tumor burden, increased
tumor regression, and delayed the progression of benign skin
tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in
metalloproteinase ADAM12 expression in skin
tumors, which in turn increased migration and
tumor cell invasiveness.