The centrosome plays an important role in maintenance of cell polarity and in progression through the cell cycle by determining the number, polarity, and organization of interphase and mitotic microtubules. By examining a set of 35 high grade human breast tumors, we show that centrosomes of adenocarcinoma cells generally display abnormal structure, aberrant protein phosphorylation, and increased microtubule nucleating capacity in comparison to centrosomes of normal breast epithelial and stromal tissues. These structural and functional centrosome defects have important implications for understanding the mechanisms by which genomic instability and loss of cell polarity develop in solid tumors.

https://www.pnas.org/content/pnas/95/6/2950.full.pdf

Centrosome hypertrophy in human breast tumors: Implications for genomic stability and cell polarity

Disclosed are new methods comprising the use of in situ hybridization to detect abnormal nucleic acid sequence copy numbers in one or more genomes wherein repetitive sequences that bind to multiple loci in a reference chromosome spread are either substantially removed and/or their hybridization signals suppressed. The invention termed Comparative Genomic Hybridization (CGH) provides for methods of determining the relative number of copies of nucleic acid sequences in one or more subject genomes or portions thereof (for example, a tumor cell) as a function of the location of those sequences in a reference genome (for example, a normal human genome). The intensity(ies) of the signals from each labeled subject nucleic acid and/or the differences in the ratios between different signals from the labeled subject nucleic acid sequences are compared to determine the relative copy numbers of the nucleic acid sequences in the one or more subject genomes as a function of position along the reference chromosome spread. Amplifications, duplications and/or deletions in the subject genome(s) can be detected. Also provided is a method of determining the absolute copy numbers of substantially all RNA or DNA sequences in subject cell(s) or cell population(s).

Comparative genomic hybridization (cgh)

Background: Biomarkers are needed to refine short-term breast cancer risk estimates from epidemiologic models and to measure response to prevention interventions. The purpose of our study was to determine whether the cytologic appearance of epithelial cells obtained from breast random periareolar fine-needle aspirates or molecular marker expression in these cells was associated with later breast cancer development. Methods: Four hundred eighty women who were eligible on the basis of a family history of breast cancer, prior precancerous biopsy, and/or prior invasive cancer were enrolled in a single-institution, prospective trial. Their risk of breast cancer according to the Gail model was calculated, and random periareolar fine-needle aspiration was performed at study entry. Cells were characterized morphologically and analyzed for DNA aneuploidy by image analysis and for the expression of epidermal growth factor receptor, estrogen receptor, p53 protein, and HER2/NEU protein by immunocytochemistry. All statistical tests are two-sided. Results: At a median follow-up time of 45 months after initial aspiration, 20 women have developed breast cancer (invasive disease in 13 and ductal carcinoma in situ in seven). With the use of multiple logistic regression and Cox proportional hazards analysis, subsequent cancer was predicted by evidence of hyperplasia with atypia in the initial fine-needle aspirate and a 10-year Gail projected probability of developing breast cancer. Although expression of epidermal growth factor receptor, estrogen receptor, p53, and HER2/NEU was statistically significantly associated with hyperplasia with atypia, it did not predict the development of breast cancer in multivariable analysis. Conclusion: Cytomorphology from breast random periareolar fine-needle aspirates can be used with the Gail risk model to identify a cohort of women at very high short-term risk for developing breast cancer. We recommend that cytomorphology be studied for use as a potential surrogate end point in prevention trials. [J Natl Cancer Inst 2000;92:1217–27]

/pdf/short-term-breast-cancer-prediction-by-random-periareolar-23i9jx5ndz.pdf

Short-Term Breast Cancer Prediction by Random Periareolar Fine-Needle Aspiration Cytology and the Gail Risk Model

Cancer serum protein profiling by mass spectrometry has uncovered mass profiles that are potentially diagnostic for several common types of cancer. However, direct mass spectrometric profiling has a limited dynamic range and difficulties in providing the identification of the distinctive proteins. We hypothesized that distinctive profiles may result from the differential expression of relatively abundant serum proteins associated with the host response. Eighty-four antibodies, targeting a wide range of serum proteins, were spotted onto nitrocellulose-coated microscope slides. The abundances of the corresponding proteins were measured in 80 serum samples, from 24 newly diagnosed subjects with lung cancer, 24 healthy controls, and 32 subjects with chronic obstructive pulmonary disease (COPD). Two-color rolling-circle amplification was used to measure protein abundance. Seven of the 84 antibodies gave a significant difference (p < 0.01) for the lung cancer patients as compared to healthy controls, as well as compared to COPD patients. Proteins that exhibited higher abundances in the lung cancer samples relative to the control samples included C-reactive protein (CRP; a 13.3 fold increase), serum amyloid A (SAA; a 2.0 fold increase), mucin 1 and α-1-antitrypsin (1.4 fold increases). The increased expression levels of CRP and SAA were validated by Western blot analysis. Leave-one-out cross-validation was used to construct Diagonal Linear Discriminant Analysis (DLDA) classifiers. At a cutoff where all 56 of the non-tumor samples were correctly classified, 15/24 lung tumor patient sera were correctly classified. Our results suggest that a distinctive serum protein profile involving abundant proteins may be observed in lung cancer patients relative to healthy subjects or patients with chronic disease and may have utility as part of strategies for detecting lung cancer.

/pdf/distinctive-serum-protein-profiles-involving-abundant-14lob0qahz.pdf

Distinctive serum protein profiles involving abundant proteins in lung cancer patients based upon antibody microarray analysis

We describe a PCR-based assay for determining c-erbB-2 oncogene amplification in breast cancer in which we use the TaqMan system Two fluorogenic probes anneal to the target between primers for c-erbB-2 and β-globin genes and contain both a reporter dye (6-carboxy-fluorescein) and a quencher dye (6-carboxy-tetramethyl-rhodamine) During the extension phase of the PCR cycle, the 5'→3' exonuclease activity of Taq polymerase cleaves the hybridized fluorogenic probe, resulting in an increase of fluorescence emission of the reporter dye that is quantitative for the amount of PCR product and, under appropriate conditions, for the amount of template Assay performance showed adequate precision and a lower detection limit and good correlation with the results obtained in the same samples by a competitive PCR assay (n = 25, r = 094, P <001) This homogeneous assay is time-saving, avoids usually cumbersome postamplification procedures (that can be additional sources of inaccuracy and contamination), and seems suitable for determination of c-erbB-2 oncogene amplification in tumor specimens

/pdf/quantitative-polymerase-chain-reaction-based-homogeneous-68551dyc5v.pdf

Quantitative polymerase chain reaction-based homogeneous assay with fluorogenic probes to measure c-erbB-2 oncogene amplification.

Background. Identifying markers that have the potential to predict tumor behavior is important in breast cancer because of the variability in clinical disease progression. Genetic alterations in tumors may appear as changes in total DNA content, individual chromosomes, single genes, or gene expression. Alteratian in DNA content is an imprecise but accessible measurement of the genome. Diploid tumors have been associated with a better clinical outcame, and increased ploidy correlates with ather indicators of poor prognosis. Concurrent analysis of DNA content with markers of genetic expression is feasible (e.g., myc oncogene) and may increase its prognostic power

Genetic markers as prognostic indicators in breast cancer.

here are several reasons why it is important to deT velop an understanding of the biology of proliferative breast disease (PBD). The most obvious is that some forms of PBD may represent precursors to malignancy, or a state of partial neoplastic transformation analogous to endometrial hyperplasia or colorectal adenoma. Although this sequence has not yet been proven, it is strongly implied by now familiar histopathologic and epidemiologic studies (1, 2). As such, PBD represents a candidate set of lesions to exploit for more precise assessments of risk for development of breast carcinoma. This is especially critical in breast neoplasia due to the inability to reliably detect and diagnose carcinomas prior to host invasion with conventional screening. In addition, PBD may also provide a target lesion to monitor during the chemoprevention protocols that are presently under investigation. Unfortunately, formidable obstacles impede meaningful investigation into the biology of PBD. Inability to serially sample breast tissue, much less lesional tissue, has obscured the histopathologic (and genetic) evolution of PBD. This problem is exacerbated by the apparent “field effect” (versus direct precursor) character of PBD, as indicated by the high frequency with which carcinomas develop in the breast contralateral to the incident hyperplastic lesion, as well as the lengthy intervals between diagnosis of PBD and subsequent malignancy. Compared to cervical dysplasia and colorectal adenoma, moreover, PBD is morphologically diverse. This not only reflects the genetic and epidemi-

Biomarkers of Proliferative Breast Disease

Human cancer: Molecular genetic and viral concepts and their influence in cytodiagnosis

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Genetic markers as prognostic indicators in breast cancer.

Biomarkers of Proliferative Breast Disease

Human cancer: Molecular genetic and viral concepts and their influence in cytodiagnosis