Apoptosis is essential for tissue development and homeostasis. When it goes wrong, one consequence can be cancer. We know little about how apoptosis is regulated in tissues, however. Why, for example, are mammary epithelial cells (MECs) growing as acini (3D tissue-like structures) in reconstituted basement membrane resistant to apoptosis? On Valerie Weaver and colleagues suggest that such cells resist apoptosis because α6β4 integrins on their surface activate the GTPase Rac, which stimulates p21-activated kinase 1 (Pak1) and consequently the anti-apoptotic signal transducer NF-κB. They have examined resistance to apoptosis in non-malignant human MECs growing on or in reconstituted basement membrane (i.e. in 2D or 3D cultures, respectively). Among their results, the authors show that inhibition of Pak1 makes mammary acini sensitive to apoptosis; this effect is reversed by expression of NF-κB. Conversely, they report, acini expressing elevated levels of Pak1 can activate NF-κB and resist apoptotic stimuli even in the absence of activated Rac. These data emphasize the importance of the basement membrane in the regulation of apoptosis and, in addition, identify Pak1 inhibitors as potential anti-tumour agents.
