hMENA11a contributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells.

Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA11a and hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA11a isoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA11a is involved in these resistance mechanisms. The specific hMENA11a depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA11a phosphorylation and affected its localization. At the functional level, we found that hMENA11a sustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA11a silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA11a contributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA11a in HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA11a expression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA11a activity could represent a new target for antiproliferative therapies in breast cancer

Involuntary Psychiatric Treatment and Other Coercive Behavioral Interventions as Criminal Sanctions: Reflections on Vitek v. Jones

This Article inquires into the substantive limits on the power of government to impose coercive behavioral interventions on criminal offenders solely because of a criminal conviction and sentence

An Everyday Lawyer’s Shakespeare

This summer, I enjoyed a unique opportunity to explore Shakespeare’s critique of law with a small group of students and a dear colleague in a study abroad program at the University of Arkansas Rome Center. I want to share my reflections on this singularly rewarding experience

Construction Law Apologetics

This Article challenges the legal academy’s perceptions and offers an alternative assessment of the relationship between the construction industry and law. Part I reviews practical reasons for teaching construction law to law students. In brief, Part I first demonstrates how a construction law course pairs advanced instruction in several topics introduced in the core curriculum, such as contracts, torts, civil procedure, evidence, remedies, and dispute resolution, with lessons on adapting legal knowledge to the specialized construction industry practice. Next, it explains how studying construction law can prepare students to represent clients in a wide range of complex commercial matters that require expertise in transactional practice, advocacy, and dispute resolution. Then, Part II makes the case for greater scholarly engagement with the legal aspects of the built environment, exploring some especially promising contract and tort topics in detail before briefly suggesting other potential research projects. Part III concludes by proposing an ongoing dialogue between construction lawyers and the legal academy

Does Sustainability Require a New Theory of Property Rights?

This is the published version

Contract Law in the Construction Industry Context

This book chronicles how contract cases from the construction industry have influenced, solidified, refined and particularized U.S. contract law. The book’s central claim is that the construction industry experience has helped to contextualize U.S. contract law and, therefore, has encouraged the common law to be more receptive to flexible legal standards and practices and less constrained by the relatively rigid rules that often characterize contract law. Other scholarly books analyze the themes, values, standards, and principles of contemporary contract law, but none captures how construction industry relationships and practices have influenced the common law of contracts. After providing an overview of construction law as a specialty of the practicing bar and as a field for scholarly inquiry, this book examines the construction industry cases that have most directly influenced contract law. It reviews how industry dispute patterns have caused courts to refine contract law principles or to adapt and modify other principles. Separate chapters explain the special roles that cases in the U.S. Supreme Court and in the lower federal courts have played in defining and distinguishing contract law in the construction industry. The final chapters assess implications the construction industry cases hold for contract theory writ large, and for the future of contract law. This book is essential reading for legal scholars, construction law and contract law specialists, and those interested in how the construction industry has helped shape the U.S. legal system