title: Cyclin D1 is a candidate oncogene in cutaneous melanoma.
abstract: The retinoblastoma pathway has been implicated in melanoma; however, previous studies of one of the key components of this pathway, cyclin D1 (CD1), failed to find amplification of this gene in a large series of melanomas. We have recently shown that a particular subtype of melanoma, acral melanoma (AM), has frequent amplification of the CD1 locus. This suggested that CD1 might be important in AM and that it may also be important in other melanoma types, even though its copy number may not be altered. We compared CD1 gene copy number and protein expression in 137 invasive primary cutaneous melanomas (71 superficial spreading melanomas, 17 nodular melanomas, 19 lentigo maligna melanomas, 18 AMs, and 12 unclassifiable melanomas) using fluorescence in situ hybridization and immunohistochemistry. We found frequent amplification of CD1 in AM (44.4%) and occasional amplification in lentigo maligna melanoma (10.5%) and superficial spreading melanoma (5.6%). CD1 protein was overexpressed in all cases with amplifications and in an additional 20% of cases without amplification. We tested the importance of CD1 in cell growth in melanoma by using adenovirus-mediated antisense treatment targeted to CD1 in two melanoma cell lines, one with and the other without CD1 amplification and overexpression. Antisense mediated down-regulation of CD1 induced apoptosis in vitro and led to significant tumor shrinkage of melanoma xenografts in severe combined immunodeficient mice. However, it did not alter the growth of normal melanocytes. Together, these results suggest that CD1 may be an oncogene in melanoma and that targeting its expression may be therapeutically beneficial.
authors.affiliation: Department of Dermatology, University of California-San Francisco, San Francisco, CA 94143, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sauter
authors.forename: Un-Cheol
authors.initials: UC
authors.lastname: Yeo
authors.forename: Andrea
authors.initials: A
authors.lastname: von Stemm
authors.forename: Weizhu
authors.initials: W
authors.lastname: Zhu
authors.forename: Samuel
authors.initials: S
authors.lastname: Litwin
authors.forename: David S
authors.initials: DS
authors.lastname: Tichansky
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Pistritto
authors.forename: Mark
authors.initials: M
authors.lastname: Nesbit
authors.forename: Dan
authors.initials: D
authors.lastname: Pinkel
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D019938:Cyclin D1