Epithelial organization is often disrupted during the development of carcinomas. Although several oncogenes have been shown to alter the localization of polarity markers in epithelial cells, the mechanisms by which this occurs are unclear. Senthil Muthuswamy and colleagues now show that the oncogenic receptor tyrosine kinase ERBB2 (also known as HER2) disrupts polarized epithelial cell organization by associating with components of the Par polarity complex.

The authors first examined the consequences of activating ERBB2 in polarized monolayers of the canine kidney epithelial cell line MDCKII. The activation of ERBB2 disrupted the polarity of these cells and induced the re-localization of the polarity protein PAR6. In polarized epithelia PAR6 is part of the Par polarity complex that contains the atypical protein kinase C (aPKC), PAR3 and CDC42, a small GTP-binding protein. In MDCKII cells, ERBB2 activation disrupted the PAR3–PAR6–aPKC–CDC42 complex by reducing the association of PAR3. Furthermore, PAR6–aPKC was recruited to the ERBB2 signalling complex.

How might ERBB2-mediated disruption of the Par polarity complex affect carcinoma development? The authors examined this using a 3-dimensional in vitro model with MCF-10A human mammary epithelial cells. The expression of ERBB2 in this system creates large multi-acinar structures with filled lumens that resemble premalignant lesions observed in the mammary glands of mice that express ERBB2. ERBB2 activation in MCF-10A acini disrupted cell polarity and led to the recruitment of PAR6–aPKC to ERBB2. The expression of a PAR6 mutant that is unable to bind aPKC blocked ERBB2-induced polarity disruption in MCF-10A cells and significantly reduced the formation of multi-acinar structures, indicating that the ERBB2–PAR6–aPKC complex is crucial for multi-acinar development.

How does the Par complex control the ability of ERBB2 to form multi-acinar structures? ERBB2-induced proliferation is the same in cells that express either wild-type or mutant PAR6, but cells that express the mutant PAR6 have much higher levels of apoptosis. This indicates that the ERBB2–PAR6–aPKC pathway is crucial for inhibiting apoptosis but does not have a role in hyperproliferation.

Finally, the authors show that the loss of another polarity protein, Scribble, can compensate for the loss of the ERBB2–PAR6–aPKC pathway, as cells that express the mutant PAR6 and SCRIB short hairpin RNAs were able to form multi-acinar structures. This indicates that the disruption of cell polarity is required for the formation of ERBB2-induced multi-acinar structures.

Muthuswamy and colleagues have shown that the deregulation of polarity proteins might have an important role in carcinoma development, and that these pathways might provide new targets for developing therapies for ERBB2-positive breast cancers.