Subtypes of breast cancer that represent the two major types of epithelial cells in the breast (luminal and basal) carry distinct histopathologic profiles. Breast cancers of the basallike subtype, which include the majority of hereditary breast cancers due to mutations in the breast cancer susceptibility gene 1 (BRCA1), frequently assume triple-negative status, i.e., they lack expression of estrogen receptor-A and progesterone receptor, and lack overexpression or amplification of the HER2/NEU oncogene. Defects in DNA damage response pathways result in genome instability and lead to carcinogenesis, but may also be exploited for therapeutic purposes. We analyzed repair of oxidative DNA damage by the base-excision repair (BER) pathway, which when aberrant leads to genomic instability and breast carcinogenesis, in cell lines that represent the different subtypes of breast cancer and in the presence of BRCA1 deficiency. We found that basal-like and BRCA1-mutated breast cancer cells were defective in BER of oxidative DNA damage, and that this defect conferred sensitivity to inhibition of poly(ADP-ribose) polymerase, a DNA repair enzyme. The defect may be attributed, at least in part, to a novel role for BRCA1 in the BER pathway. Overall, these data offer preventive, prognostic, and therapeutic usefulness. [Cancer Res 2009;69(8):3589-96]

The estrogen receptor (ER) protects against debilitating effects of the inflammatory response by inhibiting the proinflammatory transcription factor nuclear factor-kappaB (NFkappaB). Heretofore cAMP response element-binding protein (CREB)-binding protein (CBP) has been suggested to mediate inhibitory cross talk by functioning either as a scaffold that links ER and NFkappaB or as a required cofactor that competitively binds to one or the other transcriptional factor. However, here we demonstrate that ER is recruited to the NFkappaB response element of the MCP-1 (monocyte chemoattractant protein-1) and IL-8 promoters and displaces CBP, but not p65, in the MCF-7 breast cancer cell line. In contrast, ER displaced p65 and associated coregulators from the IL-6 promoter, demonstrating a gene-specific role for CBP in integrating inflammatory and steroid signaling. Further, RNA interference and overexpression studies demonstrated that CBP dosage regulates estrogen-mediated suppression of MCP-1 and IL-8, but not IL-6, gene expression. This work further demonstrates that CBP dosage is a critical regulator of gene-specific signal integration between the ER- and NFkappaB-signaling pathways.

Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of ≥20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9–74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1–38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0–25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5–34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well-tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk.

BackgroundBreast cancers due to germline mutations or altered expression of the BRCA1 gene associate with an aggressive clinical course and frequently exhibit a "triple-negative" phenotype, i.e. lack of expression of the estrogen and progesterone hormone receptors and lack of overexpression of the HER2/NEU oncogene, thereby rendering them relatively insensitive to hormonal manipulation and targeted HER2 therapy, respectively. BRCA1 plays a role in multiple DNA repair pathways, and thus, when mutated, results in sensitivity to certain DNA damaging drugs.ResultsHere, we used a Brca1 murine mammary epithelial cell (MMEC) model to examine the effect of loss of Brca1 on cellular sensitivity to various chemotherapy drugs. To explore novel therapeutic strategies, we included DNA damaging and non-DNA damaging drugs whose mechanisms are dependent and independent of DNA repair, respectively, and drugs that are used in standard and non-standard lines of therapy for breast cancer. To understand the cellular mechanism, we also determined the role that DNA repair plays in sensitivity to these drugs. We found that cisplatin and gemcitabine had the greatest specific therapeutic benefit to Brca1-deficient MMECs, and that when used in combination produced a synergistic effect. This sensitivity may be attributed in part to defective NER, which is one of the DNA repair pathways normally responsible for repairing DNA adducts produced by cisplatin and is shown in this study to be defective in Brca1-deficient MMECs. Brca1-deficient MMECs were not differentially sensitive to the standard breast cancer chemotherapy drugs doxorubicin, docetaxel or 5-FU.ConclusionsBoth cisplatin and gemcitabine should be explored in clinical trials for first line regimens for BRCA1-associated and triple-negative breast cancer.

American Society of Anesthesiologists (ASA) has introduced a simple tool to assess the perioperative risk of surgery/anesthesia in patients with obstructive sleep apnea (OSA). We compared the surgical outcomes in patients at high risk of OSA with the matched controls. This was a case-control study conducted on 3593 surgical patients receiving a general anesthesia at a single institution. On the basis of a preoperative OSA scoring system using the ASA checklist, patients were classified as high-risk OSA (HR-OSA) or low-risk OSA (LR-OSA) groups. Apnea/hypopnea index of >5 h À1 during a formal preoperative sleep study was used to confirm or rule out the diagnosis of OSA. Receiver operating characteristic curves were plotted to determine the predictive values as well as sensitivity and specificity of the ASA tool in predicting HR-OSA. The HR-OSA group was matched with the patients in LR-OSA using the propensity scoring and logistic regression. Patients were analyzed for premorbid conditions, intraoperative course and postoperative events using cross tabulation, logistic regression model and paired t test. The development of a composite respiratory complication in the postoperative period was considered as the primary end point. The ASA risk tool was found to have 95.1% sensitivity and 52.2% specificity. At a prevalence of 10%, the negative predictive value was 98.5%. Of the 3593 patients, 306 were identified as HR-OSA. The HR-OSA group was found to have a higher incidence of hypertension and diabetes preoperatively when compared with LR-OSA. Postoperatively, the HR-OSA group had higher incidence of hypoxia, reintubation, postoperative use of continuous positive airway pressure and a longer stay in the recovery room. The ASA checklist offers a highly sensitive tool to identify the patients at a higher risk of OSA during the perioperative period. Patients at HR-OSA have a higher incidence of adverse events in the postoperative period when compared with those with LR-OSA.

Background:Echinococcosis in humans occurs as a result of infection by the larval stages of taeniid cestodes of the genus echinococcus. Intracranial hydatid cysts usually develop at an intraparenchymal site. Hydatid cyst within the cerebral ventricle is quite unusual.Methods:We reviewed the literature on adult intraventricular hydatid cyst and found case reports mainly in children with an only handful of cases in adults. We reported a rare case of cerebral intraventricular (left lateral ventricle) hydatid cyst in a 21-year-old adult female.Results:Although cerebral hydatid cysts are most commonly seen in children and young adults cerebral intraventricular hydatid cyst are comparatively rarer in adults.Conclusion:The possibility of infection with Echinococcus granulosus should be included in the differential diagnosis of raised intracranial hypertension in patients from endemic areas.

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