Intact Cell Organization Resists Oncogenic Activity

HELSINKI, Aug. 28 -- Breast cancer may spring from the loss of cellular architecture that forms a barrier against oncogenes, found investigators here.
The loss of a cell polarity-regulating protein that helps maintain the architecture may be involved in the origin of breast malignancies, Juha Klefstrom, Ph.D., of the University of Helsinki, and colleagues, reported in the Aug. 28 issue of Proceedings of the National Academy of Sciences.
Experimental inhibition of the LKB1 cell polarity protein in mammary epithelial cells led to the formation of abnormal acini with an uneven, disorganized ultrastructure, they found. In acini with established epithelial organization, however, activation of the c-Myc oncogene failed to induce hyperproliferation.
"Our data show that an organized epithelial structure is a powerful restraint against oncogene-drive, unscheduled proliferation and apoptosis," the authors concluded.
Epithelial cells bind to each other by means of cell junctions and adhesions to form structured, polarized sheets anchored to a basement membrane. An organized epithelial architecture is essential for basic epithelial cell processes, such as proliferation, migration, differentiation, and death, the authors noted.
Recent evidence from Drosophila models indicates that an intact epithelial architecture also acts as a barrier to tumor development, they continued. Inactivation of genes linked to cell polarity can spontaneously induce neoplastic overgrowth or cooperation with active oncogenes.
"Rogue cancer genes can force epithelial cells to proliferate, and proliferation of malignant cells will certainly disrupt the organized epithelial structure," said Dr. Klefstrom. "However, there has always been this chicken-or-egg problem: Does a cancer gene initiate cell proliferation, which causes disruption of the epithelial structure, or does loss of tissue structure come first, creating a suitable environment for cancer genes to enforce the cell cycle progression?"
Data from their studies supports the view that loss of tissue structure occurs first, he added.
In the current study, investigators introduced an active form of c-Myc into mammary acini with established epithelial organization. The activated oncogene failed to induce changes in morphology or size or trigger proliferation.
Further studies revealed that five-day acinar structures were susceptible to the mitogenic effects of c-Myc but not 10-day structures. Notably, the authors stated, loss of susceptibility to c-Myc occurs during the period when the organized epithelial architecture forms.
Dr. Klefstrom and colleagues further elucidated the anticancer role on organized epithelial structure by examining mammary cells in a laboratory environment that strongly or weakly promoted cell differentiation. Activation of c-Myc promoted proliferation of immature cells in the former but not in the latter environment.
"The data underscore the importance of epithelial architecture and polarity in blocking the proliferative c-Myc function," the authors wrote.
The investigators then studied the effects of c-Myc in cells with intact LKB1 or experimentally silenced LKB1. The studies showed that "the absence of LKB1 leads to gross abnormalities in the structure and partial loss of cell polarity."
Additional experiments demonstrated that organized epithelial structures also resisted the apoptotic effects of the oncogene.
"We were amazed to find out that the formation of organized mammary epithelial architecture in three-dimensional organotypic cell culture correlated with complete loss of oncogenic activities of the c-Myc cancer gene," Dr. Klefstrom commented.
The authors had no disclosures. The study was funded by the Academy of Finland, the Finnish Funding Agency for Technology and Innovation, the Sigrid Juselius Foundation, Helsinki University Central Hospital, the Lilly Foundatin, and the Juliana von Wendt Foundation. Primary source: Proceedings of the National Academy of SciencesSource reference: Partanen JI et al. "Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization." PNAS 2007;104:epub.