Enhanced skin carcinogenesis in transgenic mice expressing the human cyclin D1b (CCND1b) vari

PAOLA ROJAS; FERNANDO BENAVIDES; MARCELO L. RODRIGUEZ-PUEBLA; JORGE BLANDO; CARLOS PEREZ; ADRIAN M. SENDEROWICZ; ERIK S. KNUDSEN; DAVID G. JOHNSON; CLAUDIO J. CONTI

Los Angeles, California, Estados Unidos

Congreso; American Association for Cancer Research (AACR), Centennial. Annual Meeting; 2007

American Association for Cancer Research (AACR)

Canonical cyclin D1 (cyclin D1a) regulates progression through the G1 phase of the cell cycle. A large body of literature has shown that genetic alterations of the cyclin D1 gene (CCND1) are common in human and experimental cancer [1] [2]. Overexpression, amplification, gene rearrangements, and mutations of this gene have been found in tumors of different origins [3-5]. In spite of this overwhelming correlative evidence, functional studies in vitro have not shown a strong oncogenic activity of cyclin D1. Yet, experiments in cyclin D1-null (D1 KO) mice have shown that cyclin D1 is necessary for ras-dependent tumorigenesis [6]. This paradox may be explained by the presence of an alternative splicing product of CCND1, whose formation is modulated by the G870A CCND1 polymorphism [7] Studies by three different laboratories have shown that, unlike cyclin D1a, the alternative cyclin D1b is able to transform cells in vitro and to form tumors in immunocompromised mice [11]. The majority of epidemiological studies also suggest that cyclin D1b is oncogenic. Several laboratories have shown that the G870A CCND1 polymorphism is associated with increased susceptibility and poor prognosis in human cancers, including cancer of the prostate, head and neck, urinary bladder, and colon [7,15-18]. In this study, we have developed a transgenic mouse model expressing cyclin D1b to analyze its functional significance in cancer development. The human CCND1b cDNA was placed under the control of a bovine keratin 5 (K5) promoter that constitutively expressed cyclin D1b in the basal cells of the interfollicular epidermis and the pilosebaceous unit, and to a lesser degree to other organs like thymus, pancreas, prostate and gall bladder. Interestingly, K5-cyclin D1b mice have a different phenotype than our previous K5-cyclin D1a mice, which express canonical human CCND1a under the control of K5 promoter. Whereas K5-cyclin D1a mice display strong thymic hyperplasia and moderate skin hyperplasia, K5-cyclin D1b mice do not have an evident thymic or skin phenotype. Although K5-cyclin D1b transgenic mice do not show histological alterations or develop spontaneous tumors in tissues expressing K5, they exhibited enhanced susceptibility to skin papilloma development when challenged with a chemical carcinogenesis protocol. This is additional evidence supporting the idea that cyclin D1b isoform could be oncogenic in vivo.