Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation

Abstract

Non-melanoma skin cancers, in particular keratoacanthomas (KAs) and squamous cell carcinomas (SCCs), have become highly frequent tumor types especially in immunesuppressed transplant patients. Nevertheless, little is known about essential genetic changes. As a paradigm of 'early' changes, that is, changes still compatible with tumor regression, we studied KAs by comparative genomic hybridization and show that gain of chromosome 11q is not only one of the most frequent aberration (8/18), but in four tumors also the only aberration. Furthermore, 11q gain correlated with amplification of the cyclin D1 locus (10/14), as determined by fluorescence in situ hybridization, and overexpression of cyclin D1 protein (25/31), as detected by immunohistochemistry. For unraveling the functional consequence, we overexpressed cyclin D1 in HaCaT skin keratinocytes. These cells only gained little growth advantage in conventional and in organotypic cocultures. However, although the control vector-transfected cells formed a well-stratified and orderly differentiated epidermis-like epithelium, they showed deregulation of tissue architecture with an altered localization of proliferation and impaired differentiation. The most severe phenotype was seen in a clone that additionally upregulated cdk4 and p21. These cells lacked terminal differentiation, exhibited a more autonomous growth in vitro and in vivo and even formed tumors in two injection sites with a growth pattern resembling that of human KAs. Thus, our results identify 11q13 gain/cyclin D1 overexpression as an important step in KA formation and point to a function that exceeds its known role in proliferation by disrupting tissue organization and thereby allowing abnormal growth.

Cyclin D1 and cyclin D-dependent kinases enhance oral keratinocyte proliferation but do not block keratinocyte differentiation

“…Perhaps, uncoupling these processes may require deregulation of additional pathways. For example, dermal keratinocytes that overexpress CDK4 and p21, in addition to cyclin D1 lack terminal differentiation (19). Our data are in contrast with those from other cell types where CDK6 overexpression blocks differentiation (8)(9)(10)(11)(12).…”

Cortactin expression predicts poor survival in laryngeal carcinoma

“…Moreover, treatment with combinations of chemotherapy and radiation (Forastiere et al, 2003;Vermorken et al, 2007) might be affected by FADD expression due to 11q13 amplification, as hypothesized previously (Gibcus et al, 2007b). Because amplification was proven an early event in tumorigenesis (Izzo et al, 1998;Burnworth et al, 2006), and amplicons are inherited during tumorigenesis, we hypothesize that the high occurrence of 11q13.3 amplification enables multiple genes to be beneficial to tumour progression at distinct stages of tumour development.…”

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes

“…We previously showed that loss of chromosome 15 correlated with loss of the angiogenesis inhibitor TSP-1 which in turn correlated with the angiogenic switch required for malignant conversion (Folkman and Hanahan, 1991;Bleuel et al, 1999). We recently also showed that loss of chromosome 15 occurs in human skin carcinomas and that this correlated with progression from benign to malignant tumor phenotype (Burnworth et al, 2006). Accordingly, loss of chromosome 15 seen here, may also have provided a selective advantage and thereby contributed to the high frequency of tumorigenic conversion (three out of the four different HaCaT populations irradiated with 4 Â 5 or 1 Â 20 J/cm 2 ).…”