Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification

Abstract

Cyclin D1 proto-oncogene is a key regulator of the mammalian cell-cycle acting at the restriction point in late G1. Ampli®cation of the cyclin D1 locus, located on chromosome 11q13, as well as cyclin D1 protein overexpression have been reported in several human malignancies. The purpose of this study was to evaluate cyclin D1 gene copy status and protein expression during the multistep process of head and neck tumorigenesis, using a combination of¯uorescence in situ hybridization and immunohistochemistry techniques. From 29 selected patients presenting with head and neck squamous carcinoma and whose tumor cytospins had been previously screened for presence (16 cases) or absence (13 cases) of ampli®cation at the 11q13 band, we analysed 46 para n-embedded tissue specimens that demonstrated, besides the primary tumor, the presence of contiguous adjacent normal tissue and/or premalignant lesions. Of the 16 ampli®ed cases, nine demonstrated a continuous progression from premalignant to invasive carcinoma and seven (77.7%) of these cases showed cyclin D1 gene ampli®cation in premalignant lesions prior to development of invasive carcinoma. Increased cyclin D1 protein expression was observed in all 16 ampli®ed tumors and ®ve of the 13 (38.4%) nonampli®ed tumors. Interestingly, dysregulated cyclin D1 expression was also found in the premalignant lesions adjacent to all 16 ampli®ed tumors, and it appeared to precede cyclin D1 gene ampli®cation. In contrast no dysregulated expression was detected in the premalignant lesions of the non-ampli®ed tumors. In conclusion, these ®ndings provide strong evidence for early dysregulation of cyclin D1 expression during the tumorigenesis process and suggest that dysregulated increased expression precedes and possibly enables gene ampli®cation.

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.…”

“…Considering the different functions of cortactin, cyclin D1 and FADD it would be interesting to see whether these genes, coamplified in the same tumour, have a function at specific stages of tumorigenesis. Increased expression of cyclin D1 is detected at early stages of tumorigenesis and found prior to amplification (Izzo et al, 1998). Interestingly, cyclin D1 overexpression enhances cell division and results in genomic instability (Nelsen et al, 2005).…”

Cycling to Cancer with Cyclin D1

“…Amplification of 11q13 is associated with an increasing number of adult cancers including non-small cell lung cancers 30%-46%, 47,48 head and neck squamous cell carcinomas 30-50%, [49][50][51] pancreatic carcinomas 25%, 52 bladder cancer 15% 53 pituitary adenomas 49-54%, 54,55 and breast carcinoma (13%). 56,57 While the amplicons are usually large, evidence that cyclin D1 contributes directly to the neoplastic phenotype stems from its frequency of amplification relative to other genes within the amplicon, the correlation between gene amplification and high levels of cyclin D1 protein expression and the capacity of cyclin D1 transgene to promote tumor growth in transgenic animals; 58 a property not shared by other genes located within this amplicon.…”

NFκB-Independent Signaling to the Cyclin D1 Gene by Rac

“…1 Overexpression and dysregulation of cyclin D1 is a common hallmark of numerous cancers including: breast, 2 head and neck, 3 and pancreatic. 4 The central role that cyclin D1 plays in regulation of cell cycle entry compels research into the mechanisms of its regulation.…”