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Real-time imaging reveals that noninvasive mammary epithelial acini can contain motile cells
Gray W. Pearson and Tony Hunter
Molecular and Cell Biology Laboratory, Salk Institute, La Jolla, CA 92037
Correspondence to Tony Hunter: hunter@salk.edu
To determine how extracellular signal–regulated kinases (ERK) 1/2 promote mammary tumorigenesis, we examined the real-time behavior of cells in an organotypic culture of the mammary glandular epithelium. Inducible activation of ERK1/2 in mature acini elicits cell motility and disrupts epithelial architecture in a manner that is reminiscent of ductal carcinoma in situ; however, motile cells do not invade through the basement membrane and branching morphogenesis does not take place. ERK1/2-induced motility causes cells to move both within the cell monolayer that contacts the basement membrane surrounding the acinus and through the luminal space of the acinus. E-cadherin expression is reduced after ERK1/2 activation, but motility does not involve an epithelial–mesenchymal transition. Cell motility and the disruption of epithelial architecture require a Rho kinase– and myosin light chain kinase–dependent increase in the phosphorylation of myosin light chain 2. Our results identify a new mechanism for the disruption of architecture in epithelial acini and suggest that ERK1/2 can promote noninvasive motility in preinvasive mammary tumors.
Abbreviations used in this paper: 4-HT, 4-hydroxytamoxifen; DCIS, ductal carcinoma in situ; EMT, epithelial–mesenchymal transition; ERK, extracellular signal–regulated kinase; FMI, final mean intensity; HPV, human papillomavirus; MEK, MAPK/ERK kinase; MLC, myosin light chain; MLCK, MLC kinase; ROCK, Rho kinase.
附：
美国加州：萨克生物研究学院 (Salk Institute for Biological Studies)
【简介】
Jonas Salk, the developer of the polio vaccine, established the Salk Institute for Biological Studies more than 40 years ago. His goal was to create an institute that would serve as a "crucible for creativity" to pursue questions about the basic principles of life. He wanted biologists and others to work together to explore the wider implications of their discoveries for the future of humanity.
In 1959, Salk and architect Louis Kahn began a unique partnership to design a truly distinguished research facility. Seed money was provided by the March of Dimes, which has continuously and generously supported the Salk Institute over its history. The San Diego City Council gifted the Institute with the land on which to build the facility, and this decision was approved and affirmed overwhelmingly by the people of San Diego in a special referendum.
Today, the Salk Institute conducts its biological research under the guidance of 56 faculty investigators, employing a scientific staff of more than 850, including visiting scientists, postdoctoral fellows, and graduate students. This group, recruited throughout the world, receives advice from nine distinguished nonresident fellows—influential scientists at similar institutions throughout the world.
Major areas of study focus within three areas: Molecular Biology and Genetics; Neurosciences; and Plant Biology. Knowledge acquired in Salk laboratories provides new understanding and potential new therapies and treatments for a range of diseases—from cancer to AIDS, from Alzheimer’s disease to cardiovascular disorders, from anomalies of the brain to birth defects. Studies in plant biology at the Salk may one day help improve the quality and quantity of the world’s food supply.
With the completion of the Human Genome Project, the Salk Institute is strengthening its existing programs while also moving in exciting new directions. Six key areas represent strategic research priorities: Chemistry and Proteomics; Stem Cell Biology; Cell Biology; Regulatory Biology; Metabolic Research; and Computational and Theoretical Biology.
The Salk Institute consistently ranks among the leading research institutions in the world in objective measures of the contributions of faculty and the impact of their findings. The Institute has trained more than 2,000 scientists, many of whom have gone on to positions of leadership in other prominent research centers worldwide. Five scientists trained at the Institute have won Nobel prizes, and four current resident faculty members are Nobel Laureates.
Jonas Salk's vision, coupled with the hard work and dedication of former and present Salk investigators has resulted in a unique environment where scientific discoveries have an important impact on our understanding of human health.
Basic research is truly "where cures begin ." Discoveries of the principles governing cellular activity have frequently illuminated the path toward therapies and cures. In this, Jonas Salk’s noble vision impels us still.
