Abstract

The study of in vitro morphogenesis is fundamental to understanding neoplasia since the dysregulation of morphogenic pathways that create multi-cellular organisms is a common hallmark of oncogenesis. The in vitro culture of human breast epithelial cells on reconstituted basement membranes recapitulate some features of in vivo breast development, including the formation of a three-dimensional structure termed an acinus. Importantly, the capacity to disrupt in vitro acinar morphogenesis is a common property of human breast oncogenes. In this report, we find that phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that phosphorylates phosphatidylinositol (PI) to PI(4)P, disrupts in vitro mammary acinar formation. The PI4KIIIβ protein localizes to the basal surface of acini created by human MCF10A cells and ectopic expression of PI4KIIIβ induces multi-acinar devlopment. Furthermore, expression of an oncogenic PI4KIIIβ activator, eEF1A2 (eukaryotic elongation factor 1 alpha 2), phenocopies the PI4KIIIβ multi-acinar phenotype. Ectopic expression of PI4KIIIβ or eEF1A2 alters the localization of PI(4)P and PI(4,5)P(2) within acini, indicating the importance of these lipids in acinar development. Our work shows that PI4KIIIβ, eEF1A2 and PI(4)P likely play an important role in mammary neoplasia and acinar development.

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