A hollow glandular architecture is associated with many highly organized tissues such as the mammary gland, and apoptosis functions to create this space. Now, the authors of a recent Cell paper have used non-transformed MCF-10A mammary epithelial cells in a three dimensional cell-culture model — a system in which the cells can take on many of the in vivo features of breast epithelium — to show that apoptosis is important in maintaining luminal space and that tumour cells must suppress apoptosis to successfully invade the lumen.

On studying cell death during acinar morphogenesis, the authors observed, after 5–8 days in culture, a well polarized outer layer of cells surrounding a subset of poorly polarized cells. The cells in the interior of the structure — the presumptive luminal space — died after 6–8 days, just before the lumen appeared. A lack of survival-promoting signals from the Akt pathway was implicated in this cell death, which proceeded through a caspase-dependent mechanism.

To determine whether lumen formation can occur in the absence of apoptosis, the authors overexpressed the anti-apoptotic proteins Bcl-2 and Bcl-XL. Although lumen formation was delayed, cells were eventually cleared — possibly by autophagy — and a luminal space formed. Conversely, and perhaps somewhat surprisingly, increased proliferation, which the authors induced by overexpressing cyclin D1 or human papilloma virus (HPV) 16 E7, did not fill the luminal space either. Large amounts of cellular debris and fragmented nuclei provided clues as to why this was — increased cell death was occurring.

So this begs the obvious question as to how certain oncogenes can cause cells to invade the luminal space, which occurs in early epithelial tumours. To address this, the authors cultured MCF-10A cells stably expressing either cyclin D1 with Bcl-XL, or HPV 16 E7 with Bcl-2, and found that the luminal space of acini in which both the proliferative and anti-apoptotic genes were simultaneously expressed became filled.

It seems, therefore, that only a combination of increased proliferation and decreased cell death can fill the lumen; 'isolated' biological insults induced by many cancer genes have little effect on disrupting epithelial architecture. Notably, activated ErbB2, which induces both of these biological activities, can fill the luminal space in this model system; it's also overexpressed in many metastatic breast cancers.