Negative cell cycle regulator 14-3-3sigma stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt.

The 14-3-3sigma (sigma) protein is a human cancer marker downregulated in various tumors, but its function has not been fully established. 14-3-3sigma is a negative regulator of cell cycle when overexpressed, but it is not clear whether 14-3-3sigma regulates cyclin-dependent kinase inhibitor p27(Kip1) to negatively affect cell cycle progression. Protein kinase B/Akt is a crucial regulator of oncogenic signal and can phosphorylate p27(Kip1) to enhance p27(Kip1)degradation, thereby promoting cell growth. Here, we show that 14-3-3sigma-mediated cell cycle arrest concurred with p27(Kip1) upregulation and Akt inactivation. We show that 14-3-3sigma blocks Akt-mediated acceleration of p27(Kip1) turnover rate. 14-3-3sigma inhibits Akt-mediated p27(Kip1) phosphorylation that targets p27(Kip1) for nuclear export and degradation. 14-3-3sigma inhibits cell survival and tumorigenicity of Akt-activating breast cancer cell. Low expression of 14-3-3sigma in human primary breast cancers correlates with cytoplasmic location of p27(Kip1). These data provide an insight into 14-3-3sigma activity and rational cancer gene therapy by identifying 14-3-3sigma as a positive regulator of p27 and as a potential anticancer agent.

A multi-institutional analysis of intraoperative radiotherapy for early breast cancer: Does age matter?

BACKGROUND: Single-session intraoperative radiation therapy (IORT) minimizes treatment demands associated with traditional whole breast radiation therapy (WBRT) but outcomes on local disease control and morbidity among the elderly is limited. METHODS: A multi-institutional retrospective registry was established from 19 centers utilizing IORT from 2007 to 2013. Patient, tumor, and treatment variables were analyzed for ages <70 and ≥70. RESULTS: We evaluated 686 patients (<70 = 424; ≥70 = 262) who were margin and lymph node negative. Patients <70 were more likely to have longer operative time, oncoplastic closure, higher rates of IORT used as planned boost, and receive chemotherapy and post-operative WBRT. Wound complication rates were low and not significantly different between age groups. Median follow-up was 1.06 (range 0.51-1.9) years for < 70 and 1.01 (range 0.5-1.68) years for ≥ 70. There were 5 (0.73%) breast recurrences (4 in <70 and 1 ≥ 70, p = 0.65) and no axillary recurrences during follow-up. CONCLUSIONS: IORT was associated with a low rate of wound complication and local recurrence on short-term follow-up in this cohort.

A treatment algorithm for pneumothoraces complicating central venous catheter insertion.

BACKGROUND: We investigated the role of observation or insertion of a small French pigtail catheter with Heimlich valve as alternative management to a tube thoracostomy for iatrogenic pneumothorax complicating central venous catheter (CVC) insertion. METHODS: A retrospective review of 9,637 consecutive patients who had had subclavian CVCs inserted on an outpatient basis identified 100 patients with pneumothoraces. Treatment consisted of (1) observation, (2) outpatient insertion of a Heimlich valve, or (3) inpatient tube thoracostomy. RESULTS: The median pneumothorax size was 10% (range 1% to 100%). Fifty-eight patients had observation as initial treatment, and this strategy was successful in 35 (60%). Thirty-four patients were treated initially with Heimlich valves, and this strategy was successful in 29 (85%). Tube thoracostomy as initial therapy was successful in 7 (88%) of 8 patients. Patients in who initial treatment failed were treated with insertion of a Heimlich valve or tube thoracostomy. CONCLUSION: In appropriately selected patients, pneumothorax after insertion of a subclavian CVC can be successfully managed in the outpatient setting with observation. Patients in whom observation fails can be treated with insertion of a Heimlich valve. Tube thoracostomy can be reserved for refractory PTX or emergent situations.

Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression.

14-3-3 sigma, implicated in cell cycle arrest by p53, was cloned by expression cloning through cyclin-dependent kinase 2 (CDK2) association. 14-3-3 sigma shares cyclin-CDK2 binding motifs with different cell cycle regulators, including p107, p130, p21(CIP1), p27(KIP1), and p57(KIP2), and is associated with cyclin.CDK complexes in vitro and in vivo. Overexpression of 14-3-3 sigma obstructs cell cycle entry by inhibiting cyclin-CDK activity in many breast cancer cell lines. Overexpression of 14-3-3 sigma can also inhibit cell proliferation and prevent anchorage-independent growth of these cell lines. These findings define 14-3-3 sigma as a negative regulator of the cell cycle progression and suggest that it has an important function in preventing breast tumor cell growth.

The incidence of occult nipple-areola complex involvement in breast cancer patients receiving a skin-sparing mastectomy.

BACKGROUND: Surgical treatment of breast cancer traditionally has included resection of the nipple-areola complex (NAC), in the belief that this area had a significant probability of containing occult tumors. The purpose of this study was to investigate the true incidence of NAC involvement in patients who underwent a skin-sparing mastectomy (SSM) and to determine associated risk factors. METHODS: A retrospective chart review was conducted of 326 patients who had a SSM at our institution from 1990 to 1993. NAC involvement was reviewed in 286 mastectomy specimens. The charts were analyzed for tumor size, site, histology, grade, nodal status, recurrence, survival, and NAC involvement. RESULTS: Occult tumor involvement in the NAC was found in 5.6% of mastectomy specimens (16 patients). Four patients would have had NAC involvement identified on frozen section if they had been undergoing a skin-sparing mastectomy with preservation of the NAC. There were no significant differences between NAC-positive (NAC+) and NAC-negative (NAC-) patients in median tumor size, nuclear grade, histologic subtype of the primary tumor, or receptor status. There were significant differences in location of the primary tumor (subareolar or multicentric vs. peripheral) and positive axillary lymph node status. NAC involvement was not a marker for increased recurrence or decreased survival. CONCLUSIONS: Occult NAC involvement occurred in only a small percentage of patients undergoing skin-sparing mastectomies. NAC preservation would be appropriate in axillary node-negative patients with small, solitary tumors located on the periphery of the breast.

Special considerations in breast cancer risk and survival.

Experimental and clinical evidence suggests that breast neoplasia appears to be a hormone-dependent process that may also be influenced by dietary factors in many women. Conflicting reports on the relationship between exogenous hormones and the development, progression, and recurrence of breast cancer are critically examined in this report. The absolute breast cancer risk associated with either hormone replacement therapy or oral contraceptive use has not been clearly defined. Data from some large prospective studies have actually documented lower mortality rates for women taking hormone replacement compared with those for women who did not have hormone replacement therapy. In this regard, age, duration of use, and preexisting breast cancer risk factors must be taken into account. Although the results of two major prospective clinical trials addressing the role of timing of surgery within the menstrual cycle are forthcoming, the majority of studies have found no consistent association between timing of surgery and breast cancer survival. Recently reported prospective randomized data showing that selective-estrogen-receptor-modulators can act as effective chemoprevention agents in women at increased risk for breast cancer development are presented. Finally, information regarding the effect of dietary manipulation on breast cancer risk and survival is reviewed.