title: Identification and functional analysis of 9p24 amplified genes in human breast cancer.
abstract: Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16(INK4a), p21(Waf1/Cip1) and p27(Kip1). Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.
authors.affiliation: Breast Cancer Program, Wayne State University, Detroit, MI 48201, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Dombkowski
authors.forename: J
authors.initials: J
authors.lastname: Abrams
authors.forename: R
authors.initials: R
authors.lastname: Martin-Trevino
authors.forename: M S
authors.initials: MS
authors.lastname: Wicha
authors.forename: S P
authors.initials: SP
authors.lastname: Ethier
authors.forename: Z-Q
authors.initials: ZQ
authors.lastname: Yang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D010447:Peptide Hydrolases / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C436291:CDKN1B protein, human; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C570899:DMAC1 protein, human; D020662:Guanine Nucleotide Exchange Factors; C413655:KDM4C protein, human; D008565:Membrane Proteins; C505231:RIC1 protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D056484:Jumonji Domain-Containing Histone Demethylases; C465619:UHRF2 protein, human; D044767:Ubiquitin-Protein Ligases; C570900:ERMP1 protein, human; D010447:Peptide Hydrolases