Epiregulin contributes to breast tumorigenesis through regulating matrix metalloproteinase 1 and promoting cell survival.

BACKGROUND: The epidermal growth factor (EGF) family of ligands has been implicated in promoting breast cancer initiation, growth and progression. The contributions of EGF family ligands and their receptors to breast cancer are complex, and the specific mechanisms through which different ligands regulate breast tumor initiation and growth are not well-defined. These studies focus on the EGF family member epiregulin (EREG) as a mediator of early stage breast tumorigenesis. METHODS: EREG expression levels were assessed in both cell lines and human samples of ductal carcinoma in situ (DCIS) using quantitative RT-PCR, ELISA and immunohistochemistry. Gene knock-down approaches using shRNA-based strategies were used to determine the requirement of EREG for growth of MCF10DCIS cells in vivo, and for identifying mechanisms through which EREG promotes tumor cell survival. Experiments were performed using a combination of two-dimensional culture, three-dimensional culture and tumor growth in vivo. RESULTS: In comparison with other EGF family members, EREG was induced in MCF10DCIS cells compared with MCF10A and MCF10AT cells and its expression was partially regulated by fibroblast growth factor receptor (FGFR) activity. Reduced EREG expression in MCF10DCIS cells led to decreased tumor growth in vivo, which was associated with reduced cell survival. Furthermore, treatment of MCF10A cells with exogenous EREG enhanced cell survival both in three-dimensional culture and in response to chemotherapeutic agents. Examination of EREG-induced signaling pathways demonstrated that EREG promoted survival of MCF10A cells through regulating expression of matrix metalloproteinase-1 (MMP-1). To determine the relevance of these findings in human tumors, samples of DCIS were analyzed for EREG and MMP-1 expression. EREG was induced in DCIS lesions compared to normal breast epithelium, and EREG and MMP-1 were correlated in a subset of DCIS samples. CONCLUSIONS: Together, these studies lead to identification of a novel pathway involving EREG and MMP-1 that contributes to the formation of early stage breast cancer. Understanding these complex pathways could ultimately lead to the development of novel biomarkers of neoplastic progression and/or new therapeutic strategies for patients with early stage cancer.

Undergraduate, Nonmedical Students can Pass the FLS Manual Skills Exam With Minimal Practice.

OBJECTIVES: The primary objective of this study is to investigate whether undergraduate, nonmedical students could pass the FLS Manual Skills Exam with minimal practice. The secondary objective is to examine ACGME case log data from graduating chief residents over the past 18 years to examine how laparoscopic experience has evolved over that time period. DESIGN: Undergraduate, nonmedical students received training and unlimited practice time before being tested on each task of the FLS Manual Skills Exam. Each task was timed and scored using the MISTELS system. ACGME case log data from graduating chief residents over the past 18 years was obtained. SETTING: The setting is SimPortal, the simulation center associated with the University of Minnesota Medical School. PARTICIPANTS: The participants are 25 undergraduate, nonmedical students from the University of Minnesota. Participants were recruited on campus. RESULTS: Twenty-three out of 25 (92%) undergraduate, nonmedical students successfully completed one attempt for each task of the FLS Manual Skills Exam and 21 out of 25 (84%) completed both attempts. The average total practice time was 39 minutes. Over the past 18 years, the average number of laparoscopic cases completed by a graduating chief increased from 142 to 275 cases (93% increase). Additionally, the average number of cases of the top 5 most common laparoscopic operations increased from 25% to over 400%. CONCLUSIONS: Undergraduate, nonmedical students can pass the FLS Manual Skills Exam with minimal practice. Additionally, general surgery residents and medical students continue to gain more laparoscopic experience throughout medical training as laparoscopic surgery is utilized for more operations. The FLS Manual Skills Exam should be re-examined to determine its utility as a high-stakes exam.

ADAM17 in tumor associated leukocytes regulates inflammatory mediators and promotes mammary tumor formation.

The presence of inflammatory cells within the tumor microenvironment has been tightly linked to mammary tumor formation and progression. Specifically, interactions between tumor cells and infiltrating macrophages can contribute to the generation of a pro-tumorigenic microenvironment. Understanding the complex mechanisms that drive tumor cell-macrophage cross-talk will ultimately lead to the development of approaches to prevent or treat early stage breast cancers. As described here, we demonstrate that the cell surface protease a disintegrin and metalloproteinase 17 (ADAM17) is expressed by macrophages in mammary tumors and contributes to regulating the expression of pro-inflammatory mediators, including inflammatory cytokines and the inflammatory mediator cyclooxygenase-2 (Cox-2). Furthermore, we demonstrate that ADAM17 is expressed on leukocytes, including macrophages, within polyoma middle T (PyMT)-derived mammary tumors. Genetic deletion of ADAM17 in leukocytes resulted in decreased onset of mammary tumor growth, which was associated with reduced expression of the Cox-2 within the tumor. These findings demonstrate that ADAM17 regulates key inflammatory mediators in macrophages and that leukocyte-specific ADAM17 is an important promoter of mammary tumor initiation. Understanding the mechanisms associated with early stage tumorigenesis has implications for the development of preventive and/or treatment strategies for early stage breast cancers.