Lung cancer is a leading cause of cancer death, where the amplification of oncogenes contributes to tumorigenesis. Genomic profiling of 128 lung cancer cell lines and tumors revealed frequent focal DNA amplification at cytoband 14q13.3, a locus not amplified in other tumor types. The smallest region of recurrent amplification spanned the homeobox transcription factor TITF1 (thyroid transcription factor 1; also called NKX2-1), previously linked to normal lung development and function. When amplified, TITF1 exhibited increased expression at both the RNA and protein levels. Small interfering RNA (siRNA)-mediated knockdown of TITF1 in lung cancer cell lines with amplification led to reduced cell proliferation, manifested by both decreased cell-cycle progression and increased apoptosis. Our findings indicate that TITF1 amplification and overexpression contribute to lung cancer cell proliferation rates and survival and implicate TITF1 as a lineage-specific oncogene in lung cancer.

DNA amplifications and deletions frequently contribute to the development and progression of lung cancer. To identify such novel alterations in small cell lung cancer (SCLC), we performed comparative genomic hybridization on a set of 24 SCLC cell lines, using cDNA microarrays representing B22 000 human genes (providing an average mapping resolution of o70 kb). We identified localized DNA amplifications corresponding to oncogenes known to be amplified in SCLC, including MYC (8q24), MYCN (2p24) and MYCL1 (1p34). Additional highly localized DNA amplifications suggested candidate oncogenes not previously identified as amplified in SCLC, including the antiapoptotic genes TNFRSF4 (1p36), DAD1 (14q11), BCL2L1 (20q11) and BCL2L2 (14q11). Likewise, newly discovered PCR-validated homozygous deletions suggested candidate tumor-suppressor genes, including the proapoptotic genes MAPK10 (4q21) and TNFRSF6 (10q23). To characterize the effect of DNA amplification on gene expression patterns, we performed expression profiling using the same microarray platform. Among our findings, we identified sets of genes whose expression correlated with MYC, MYCN or MYCL1 amplification, with surprisingly little overlap among gene sets. While both MYC and MYCN amplification were associated with increased and decreased expression of known MYC upregulated and downregulated targets, respectively, MYCL1 amplification was associated only with the latter. Our findings support a role of altered apoptotic balance in the pathogenesis of SCLC, and suggest that MYC family genes might affect oncogenesis through distinct sets of targets, in particular implicating the importance of transcriptional repression.

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DNA amplifications in breast cancer are frequent on chromosome 11q, in which multiple driver oncogenes likely reside in addition to cyclin D1 (CCND1). One such candidate, the scaffolding adapter protein, GRB2-associated binding protein 2 (GAB2), functions in ErbB signaling and was recently shown to enhance mammary epithelial cell proliferation, and metastasis of ERBB2 (HER2/neu)-driven murine breast cancer. However, the amplification status and function of GAB2 in the context of amplification remain undefined. In this study, by genomic profiling of 172 breast tumors, and fluorescence in situ hybridization validation in an independent set of 210 scorable cases, we observed focal amplification spanning GAB2 (11q14.1) independent of CCND1 (11q13.2) amplification, consistent with a driver role. Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. GAB2 knockdown also reduced proliferation and survival in a cell line (BT474) with ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate focal amplification of GAB2 in breast carcinogenesis, and underscore an oncogenic role of scaffolding adapter proteins, and a potential new point of therapeutic intervention.Oncogene ( Keywords: GAB2; DNA amplification; genomic profiling; array-based comparative genomic hybridization; breast cancer; oncogene dependency Breast cancer is the second leading cause of cancer death in women in the United States (Jemal et al., 2007), affecting all races and ethnicities. Breast cancer develops through multiple genetic alterations, including amplification and resultant overexpression of oncogenes. The discovery and characterization of amplified oncogenes informs the understanding of breast cancer pathogenesis, and provides useful biomarkers and therapeutic targets. This is best exemplified by ERBB2 (Her2/neu; 17q12), a receptor tyrosine kinase amplified in 20-30% of breast cancers and the target of molecularly directed therapies, such as trastuzumab (Pegram et al., 2000).The chromosomal region 11q13-q14 is amplified in 15-20% of breast cancers, and the finding of distinct loci amplified independently or in combination suggests the presence of multiple 'driver' oncogenes (Karlseder et al., 1994;Ormandy et al., 2003). Within the proximal (that is, more centromeric) region, cyclin D1 (CCND1; at 11q13.2) has been considered the main driver, promoting G1-to S-phase cell-cycle progression. Other candidate oncogenes frequently co-amplified at 11q13.2 include fibroblast growth factor-3 (also called int-2) and cortactin (EMSI) (Karlseder et al., 1994). More distally, EMSY (at 11q13.5), encoding a binding partner of breast cancer 2, early onset (BRCA2), has been nominated as an amplicon ...

Optical transmission and reflection spectra (mid ir through uv) and Raman spectra of superior-quality 90-, 180-, 400-, and 1000-nm-thick superconducting Y-Ba-Cu-O films are reported. Characteristic excitonic bands, and in particular the absorption band at -0.37 eV reported earlier, are not observed. It therefore seems unlikely that the high-TV superconductivity in cuprates could arise from excitonmediated electron pairing.PACS numbers: 74.70.Ya, 78.30.Er The discovery of high-TV superconductivity in cuprates 1 has stimulated unprecedented research activity. Much of the effort is focused on understanding the underlying mechanism of the superconductivity, and a number of models have already been proposed. 2 " 4 Some of them are specific enough to be directly tested experimentally. However, what is usually the most powerful technique for identifying the mechanism, tunneling spectroscopy, has been greatly hampered so far by the generally bad surface quality of the presently available oxygen-annealed cuprate pellets and films. Infrared spectroscopy probes much deeper into the bulk of the sample and thus could play an important role in the clarification of the mechanism of superconductivity in these materials.The optical reflectivity spectra of La-Sr-Cu-O and YBa-Cu-O have been measured 5 " 7 over a broad frequency range (far ir through uv). However, since reflectivity depends on both the real and the imaginary parts of the dielectric function, such spectra cannot be interpreted directly in general. Orenstein et al. 5 tried to fit their data by the simple classical Drude model, e(co) = e(oo) -ca^/coico + ir); their optimal parameter values were ^=2 and 3 eV for La-Sr-Cu-O and Y-Ba-Cu-O, respectively, and r=0.5 eV and e(°°)=4.5 for both compounds. The calculated reflectivity turned out to be much too large in the mid-ir and near-ir region (0.1 to 1 eV). Orenstein et al. 5 concluded that an optically allowed transition across a gap occurs at -0.5 eV in LaSr-Cu-O; a similar result was obtained for Y-Ba-Cu-O. Therefore, they inferred that the corresponding strong absorption band (with the peak absorption coefficient of -10 5 cm -1 ) should be directly observable in transmission experiments on thin films. Finally, they found this ir feature to be absent in undoped La2Cu04, thus tying it to superconductivity. Etemad et al. 5 also found the correlation between the occurrence of the 0.5-eV peak and superconductivity in La2-^Sr x Cu04. Kamaras et al., 6 by an analogous methodology, concluded that two strong electronic transitions occur at 0.44 and 1.3 eV in La-Ba-Cu-O, and at 0.37 and 2.5 eV in Y-Ba-Cu-O. In oxygen-depleted (nonsuperconducting) YBa2Cu306.2 samples, the 0.37-eV peak was absent. They interpreted these spectral features as the charge-transfer-exciton bands, in support of the excitonic superconductivity model of Varma et al. 2 Finally, Schlesinger et al. 7 also recorded similar spectra but derived just the opposite conclusion. Inspired by the recent report 8 of singlecrystal La2Ni04 reflectivity spectra, which ...

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