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Breast cancer exhibits clinical and molecular heterogeneity, where expression profiling studies have identified five major molecular subtypes. The basal-like subtype, expressing basal epithelial markers and negative for estrogen receptor (ER), progesterone receptor (PR) and HER2, is associated with higher overall levels of DNA copy number alteration (CNA), specific CNAs (like gain on chromosome 10p), and poor prognosis. Discovering the molecular genetic basis of tumor subtypes may provide new opportunities for therapy. To identify the driver oncogene on 10p associated with basal-like tumors, we analyzed genomic profiles of 172 breast carcinomas. The smallest shared region of gain spanned just seven genes at 10p13, including calcium/calmodulin-dependent protein kinase ID (CAMK1D), functioning in intracellular signaling but not previously linked to cancer. By microarray, CAMK1D was overexpressed when amplified, and by immunohistochemistry exhibited elevated expression in invasive carcinomas compared to carcinoma in situ. Engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells led to increased cell proliferation, and molecular and phenotypic alterations indicative of epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion. Our findings identify CAMK1D as a novel amplified oncogene linked to EMT in breast cancer, and as a potential therapeutic target with particular relevance to clinically unfavorable basal-like tumors.
Mol Oncol 2008 Dec
PMID:CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer. 1938 54

Although abscisic acid (ABA) and ethylene have antagonistic functions in the control of plant growth and development, including seed germination and early seedling development, it remains unknown whether a convergent point exists between these two signaling pathways or whether they operate in parallel in Arabidopsis thaliana. To elucidate this issue, four ethylene mutants, ctr1, ein2, ein3, and ein6, were crossed with aba2 (also known as gin1-3) to generate double mutants. Genetic epistasis analysis revealed that all of the resulting double mutants displayed aba2 mutant phenotypes with a small plant size and wiltiness when grown in soil or on agar plates. Further ethylene sensitivity or triple response analyses demonstrated that these double mutants also retained the ctr1 or ein mutant phenotypes, showing ethylene constitutive triple and insensitive responses, respectively. Our current data therefore demonstrate that ABA and ethylene act in parallel, at least in primary signal transduction pathways. Moreover, by microarray analysis we found that an ACC oxidase (ACO) was significantly upregulated in the aba2 mutant, whereas the 9-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (NCED3) gene in ein2 was upregulated, and both the ABSCISIC ACID INSENSITIVE1 (ABI1) and cytochrome P450, family 707, subfamily A, polypeptide 2 (CYP707A2) genes in etr1-1 were downregulated. These data further suggest that ABA and ethylene may control the hormonal biosynthesis, catabolism, or signaling of each other to enhance their antagonistic effects upon seed germination and early seedling growth.
Plant Mol Biol 2009 Sep
PMID:Antagonism between abscisic acid and ethylene in Arabidopsis acts in parallel with the reciprocal regulation of their metabolism and signaling pathways. 1951 6

Oral cancer develops through a series of histopathological stages: through mild (low grade), moderate, and severe (high grade) dysplasia to carcinoma in situ and then invasive disease. Early detection of those oral premalignant lesions (OPLs) that will develop into invasive tumors is necessary to improve the poor prognosis of oral cancer. Because no tools exist for delineating progression risk in low grade oral lesions, we cannot determine which of these cases require aggressive intervention. We undertook whole genome analysis by tiling-path array comparative genomic hybridization for a rare panel of early and late stage OPLs (n = 62), all of which had extensive longitudinal follow up (>10 years). Genome profiles for oral squamous cell carcinomas (n = 24) were generated for comparison. Parallel analysis of genome alterations and clinical parameters was performed to identify features associated with disease progression. Genome alterations in low grade dysplasias progressing to invasive disease more closely resembled those observed for later stage disease than they did those observed for non-progressing low grade dysplasias. This was despite the histopathological similarity between progressing and non-progressing cases. Strikingly, unbiased computational analysis of genomic alteration data correctly classified nearly all progressing low grade dysplasia cases. Our data demonstrate that high resolution genomic analysis can be used to evaluate progression risk in low grade OPLs, a marked improvement over present histopathological approaches which cannot delineate progression risk. Taken together, our data suggest that whole genome technologies could be used in management strategies for patients presenting with precancerous oral lesions.
Mol Cancer 2009 Jul 23
PMID:Genomic imbalances in precancerous tissues signal oral cancer risk. 1962 13

Somatic mutations of PIK3CA are found in 20% to 40% of invasive breast cancers. To investigate the frequency of PIK3CA mutations in the intraductal proliferative lesions of the breast, which are precursor lesions for invasive carcinoma, we analyzed 125 intraductal proliferative lesions and 108 invasive breast cancer tissues for PIK3CA mutations in this study. Target cells were precisely isolated using a laser capture microdissection (LCM) system. Genomic DNA was extracted with QIAmp DNA Micro Kit. PCR amplification was done for exons 9 and 20 of PIK3CA, where 90% of mutations clustered, and the products were directly sequenced. Forty-six missense mutations were identified in total, of which, 14 and 32 mutations clustered in exon 9 and exon 20, respectively. The most common mutations were E542K (6 cases) and E545K (8 cases) in exon 9, and H1047R (29 cases) in exon 20. A novel mutation, G3292T, was also found. Mutations were found less frequently in the ductal intraepithelial neoplasia 1B (DIN1B) and lower grade ductal proliferative lesions (3 of 68; 4.41%) than in ductal carcinoma in situ (14 of 57; 24.56%, P=0.001, Chi-square test) or invasive carcinoma (29 of 108; 26.85%, P=0.000, Chi-square test). However, there was no significant difference in the frequency of PIK3CA mutations between carcinoma in situ and invasive carcinoma (P=0.750, Chi-square test). PIK3CA mutations mostly began to develop at the stage from the DIN1B to the carcinoma in situ (DCIS), which is a late event of breast oncogenesis. PIK3CA-mutated tumors were more frequently found in ER-a positive, PR positive, and PTEN positive tumors (P=0.012, P=0.004 and P=0.004, respectively, Chi-square test). The frequency of PIK3CA gene mutation in ER+/PR+ (32/98, 32.65%) tumors was not significantly different from that in ER+/PR- (9/39, 23.08%), tested by the Chi-square test (P=0.269). There was no significant association between PIK3CA mutations and HER2 expression status (P=0.294, Chi-square test).
Exp Mol Pathol 2010 Feb
PMID:PIK3CA mutations mostly begin to develop in ductal carcinoma of the breast. 1981 61

The absorption and emission spectroscopic investigations of the C-8-phenyl substituted analogue of the pyrromethene dye PM567 in various polar, non-polar as well as protic and aprotic solvents are reported. The solvatochromic shifts of the spectral bands were studied in a multitude of polar, non-polar and protic, aprotic solvents followed by a multilinear regression in which several solvent parameters were simultaneously analysed. Comparison of the experimental results with those obtained by gas phase ab initio computation with CIS, TD-HF and TD-DFT theories using 6-31G* basis set reveal an overestimation of the experimentally measured excitation parameters by all these theoretical models. However, the trends in the experimental results agree with those calculated theoretically.
Spectrochim Acta A Mol Biomol Spectrosc 2010 Feb
PMID:Photophysical properties of the 8-phenyl analogue of PM567: a theoretical rationalization. 2000 21

The transcription factor Forkhead box M1 (FOXM1) is a key regulator of cell proliferation and is overexpressed in many forms of primary cancers, leading to uncontrolled cell division and genomic instability. To address the role of FOXM1 in chemoresistance, we generated a cisplatin-resistant breast cancer cell line (MCF-7-CIS(R)), which had an elevated level of FOXM1 protein and mRNA expression relative to the parental MCF-7 cells. A close correlation was observed between FOXM1 and the expression of its proposed downstream targets that are involved in DNA repair; breast cancer-associated gene 2 (BRCA2) and X-ray cross-complementing group 1 (XRCC1) were expressed at higher levels in the resistant cell lines compared with the sensitive MCF-7 cells. Moreover, cisplatin treatment induced DNA damage repair in MCF-7-CIS(R) and not in MCF-7 cells. Furthermore, the expression of a constitutively active FOXM1 (DeltaN-FOXM1) in MCF-7 cells alone was sufficient to confer cisplatin resistance. Crucially, the impairment of DNA damage repair pathways through the small interfering RNA knockdown inhibition of either FOXM1 or BRCA2/XRCC1 showed that only the silencing of FOXM1 could significantly reduce the rate of proliferation in response to cisplatin treatment in the resistant cells. This suggests that the targeting of FOXM1 is a viable strategy in circumventing acquired cisplatin resistance. Consistently, the FOXM1 inhibitor thiostrepton also showed efficacy in causing cell death and proliferative arrest in the cisplatin-resistant cells through the downregulation of FOXM1 expression. Taken together, we have identified a novel mechanism of acquired cisplatin resistance in breast cancer cells through the induction of FOXM1.
Mol Cancer Res 2010 Jan
PMID:FOXM1 confers acquired cisplatin resistance in breast cancer cells. 2006 70

Effects of solvent polarity on the photophysical behaviour of meso-tetra-2-chlorophenylporphyrin have been studied by means of steady-state absorption and fluorescence, as well as time-resolved fluorescence techniques. A non-mirror symmetric absorption and emission spectra due to vibronic borrowing were obtained. Time-resolved fluorescence study indicated the bi-exponential decay kinetics for both the emission bands, observed in steady-state emission spectra. Such findings implied that there exists two emitting species on the photoinduced conformational excursions of the excited-state equilibrium and also that their relative contributions to emission change with solvent polarity. Monte Carlo conformational search based on force-field molecular mechanics was performed to locate equilibrium conformers in the ground state which enable evaluation of the ground-state barrier energies. This was followed by CIS and ZINDO calculations to explore the excited-state barriers.
Spectrochim Acta A Mol Biomol Spectrosc 2010 Jul
PMID:Environmental effects on luminescence of meso-tetra-2-chlorophenylporphyrin. 2037 Dec 8

Bladder cancer is one of the most expensive cancers from diagnosis to death of the patient due to life-long surveillance involving upper tract imaging, urinary cytology, and cystoscopy. Cytology has been historically used in conjunction with cystoscopy to help detect disease that may be missed by routine cystoscopy (e.g., carcinoma in situ and upper tract disease). Urine cytology is highly cytopathologist dependent and has reasonable sensitivity for detecting high grade disease. However, its sensitivity drops precipitously with regard to well-differentiated low grade cancers. Intensive investigations have been undertaken using proteomics to find an alternative to cystoscopy and cytology. Urine proteomic markers currently evaluated critically in the literature include bladder tumor antigen, nuclear matrix protein 22, BLCA-4, hyaluronic acid, hyaluronidase, cytokeratin 8, cytokeratin 18, cytokeratin 19, tissue polypeptide antigen, and tissue polypeptide-specific antigen. Markers used as alternatives to cystoscopy must be accurate with high sensitivity and specificity, cost effective for life-long surveillance, and minimally invasive to minimize the burden to the patient. To date, no proteomic marker has been developed that can replace cystoscopy for the detection of bladder cancer. However, several urinary markers appear to have higher sensitivity albeit lower specificity than cytology and can be used to supplement cystoscopy. Some of those markers are herein described in this chapter. By defining and characterizing the current state of the art in protein based markers, we are poised to evaluate and benchmark newly discovered protein biomarkers that will be isolated through new proteomics based investigations of urine.
Methods Mol Biol 2010
PMID:Proteomic assays for the detection of urothelial cancer. 2040 54

The rat lung cancers induced by 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN) are considered to be a good model for illustrating genetic alterations in human lung precancerous and cancerous lesions. Recently, we had reported that the model can also be used to investigate the step-by-step dynamic changes in DNA methylation during lung carcinogenesis. In this study, we have used the same animal model to further study the evolution of methylation alterations of cell cycle regulatory genes CDKN1B (p27) and CDKN1C (p57). Our results showed epigenetic alterations in p27 and p57. Promoter hypermethylation of p27 was detected in one sample of carcinoma in situ (CIS) and two samples of infiltrating carcinoma, all three of which lacked expression of the p27 protein. Methylation of the p57 promoter correlated with the loss of protein expression in lung pathologic lesions, with a gradual increase in methylation frequency from 0 sample in the normal epithelium and hyperplasia, to 11.1% in squamous metaplasia, 18.9% in dysplasia, 26.7% in CIS, and finally 36.0% in infiltrating carcinoma samples. Immunohistochemical analysis showed that p27 and p57 protein expression decreased as lung carcinogenesis progressed. Moreover, weak expression of p27 and p57 in methylated primary tumor cell lines increased markedly after treatment with 5-aza-2'-deoxycytidine (5-aza-dC), confirming that methylation was indeed responsible for the gene downregulation. These results suggest that the progression of rat lung carcinogenesis induced by MCA/DEN is associated with dynamic changes in promoter hypermethylation of cell cycle regulatory genes, including p27 and p57, accounting for their defective expression.
Mol Carcinog 2010 Jun
PMID:Epigenetic silencing of cell cycle regulatory genes during 3-methylcholanthrene and diethylnitrosamine-induced multistep rat lung cancer. 2051 41

During carcinogenesis it is known that growth factors and cytokines from stromal and inflammatory cells from the microenvironment promote angiogenesis and lymphangiogenesis. However, the participation of macrophages and mast cells in these processes is not well understood. The aim of this study was to evaluate the relationship between mast cell and macrophage density with blood and lymphatic vessels in various stages of carcinoma of the uterine cervix. Tissue sections from archival paraffin-embedded samples from cases with cervical intraepithelial neoplasias (CIN) 1, 2, 3, carcinoma in situ, and invasive carcinoma were used. Immunohistochemical staining was done using the following antibodies: anti-LYVE-1; anti-CD31; anti-CD68, and anti-tryptase. Our results showed a significant increase in the number of macrophages in carcinoma in situ, a correlation between lymphatic vessels and macrophages in premalignant lesions CIN 2, and a correlation between mast cells and blood vessels in both CIN 2 and carcinoma in situ. In conclusion, our data underscore the importance of the recruitment of macrophages and mast cells in the development of tumor-associated blood and lymphatic capillaries.
Exp Mol Pathol 2010 Oct
PMID:The role of macrophages and mast cells in lymphangiogenesis and angiogenesis in cervical carcinogenesis. 2059 41


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