Aurora a and B overexpression and centrosome amplification in early estrogen-induced tumor foci in the Syrian hamster kidney: implications for chromosomal instability, aneuploidy, and neoplasia

Estrogen-induced Syrian hamster tumors in the kidney represent a useful model to gain insight into the role of estrogens in oncogenic processes. We provided evidence that early tumor foci in the kidney arise from interstitial ectopic uterine-like germinal stem cells, and that early tumor foci and well-established tumors are highly aneuploid (92-94%). The molecular mechanisms whereby estrogens mediate this process are unclear. Here, we report that estrogen treatment induced significant increases in Aurora A protein expression (8.7-fold), activity (2.6-fold), mRNA (6.0-fold), and Aurora B protein expression (4.6-fold) in tumors, compared with age-matched cholesterol-treated kidneys. Immunohistochemistry revealed that this increase in Aurora A and B protein expression was essentially confined to cells within early and large tumor foci at 3.5 and 6 months of estrogen treatment, respectively. Upon estrogen withdrawal or coadministration of tamoxifen for 10 days, a 78% to 79% and 81% to 64% reduction in Aurora A and B expression, respectively, were observed in primary tumors compared with tumors continuously exposed to estrogens. These data indicate that overexpressed Aurora A and B in these tumors are under estrogen control via estrogen receptor alpha. Aurora A coenriched with the centrosome fraction isolated from tumors in the kidney. Centrosome amplification (number and area/cell) was detected in early tumor foci and large tumors but not in adjacent uninvolved or age-matched control kidneys. Taken together, these data indicate that persistent overexpression of Aurora A and B is under estrogen control, and is coincident with centrosome amplification, chromosomal instability, and aneuploidy, and represent an important mechanism driving tumorigenesis.     

Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy

Metaplastic breast carcinoma, a rare tumor composed of adenocarcinomatous and nonglandular growth patterns, is characterized by a propensity for distant metastases and resistance to standard anticancer therapies. We sought confirmation that this tumor is a basal-like breast cancer, expressing epidermal growth factor receptor (EGFR) and stem cell factor receptor (KIT). EGFR activating mutations and high copy number (associated with response to tyrosine kinase inhibitor gefitinib) and KIT activating mutations (associated with imatinib sensitivity) were then investigated. Seventy-seven metaplastic cases were identified (1976-2006); 38 with tumor blocks available underwent pathologic confirmation before EGFR and KIT immunohistochemical analyses. A tissue microarray of malignant glandular and metaplastic elements was constructed and analyzed immunohistochemically for cytokeratin 5/6, estrogen receptor, progesterone receptor, and p63, and by fluorescence in situ hybridization for EGFR and HER-2/neu. DNA isolated from individual elements was assessed for EGFR and KIT activating mutations. All assessable cases were negative for estrogen receptor, progesterone receptor, and (except one) HER2. The majority were positive for cytokeratin 5/6 (58%), p63 (59%), and EGFR overexpression (66%); 24% were KIT positive. No EGFR or KIT activating mutations were present; 26% of the primary metaplastic breast carcinomas were fluorescence in situ hybridization-positive, displaying high EGFR copy number secondary to aneusomy (22%) and amplification (4%). We report here that metaplastic breast carcinoma is a basal-like breast cancer lacking EGFR and KIT activating mutations but exhibiting high EGFR copy number (primarily via aneusomy), suggesting that EGFR tyrosine kinase inhibitors should be evaluated in this molecular subset of breast carcinomas.     

Effects of primary glaucoma on sleep quality and daytime sleepiness of patients residing at an equatorial latitude

AIM: To investigate the efficacy and the safety of umbilical cord derived mesenchymal stem cell (UC-MSC) implantation in patients with retinitis pigmentosa (RP). METHODS: This prospective, single-center, phase 3 clinical study enrolled 124 eyes of 82 RP patients. The patients received 5 million UC-MSCs to the suprachoroidal area with a surgical procedure. Patients were evaluated on the 1st day, 1st and 6th month postoperatively. Best corrected visual acuity (BCVA), anterior segment and fundus examinations, color photography, optical coherence tomography (OCT), and visual ?eld (VF) tests were carried out at each visit. Fundus ?uorescein angiography (FFA) and multifocal electroretinography (mfERG) recordings were performed at the end of the 6th month. Ocular and systemic adverse events of the surgical procedure were also noted. RESULTS: All of the 82 patients completed the 6-month follow-up period. None of them had any serious systemic or ocular complications. There were statistically significant improvements in BCVA and VF during the study (all P<0.05). The amplitudes of the P1 waves in the central areas showed significant improvements in mfERG recordings. There were also significant increases in implicit times of P1 waves in the central areas. CONCLUSION: Suprachoroidal administration of UC-MSCs has beneficial effect on BCVA, VF, and mfERG measurements during the 6-month follow-up period. Cell mediated therapy based on the secretion of growth factors (GFs) seems to be an effective and safe option for degenerative retinal diseases.