Molecular control of apoptosis in the breast

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Understanding the molecular control of apoptosis in breast epithelium represents an exciting new challenge in breast biology. As a prerequisite for unravelling potential mechanisms for apoptotic defects in neoplasia of the breast, we have opted to decipher its regulation in normal mammary epithelium. Apoptosis occurs naturally at several stages of breast development; during the formation of intraductal lumina, at the end of each menstrual/oestrus cycle, and during involution that follows lactation. In the latter case, experimental manipulation of nursing can result in massive and synchronised epithelial cell apoptosis. Moreover, the culture of primary breast epithelial explants can be manipulated to allow synchronous apoptosis. We have used these experimental systems to define both extracellular regulators of survival and the intracellular components of the Bcl-2 family that are involved with apoptotic decisions in mammary epithelium.

It is well known that soluble factors are essential for cell survival, and both EGF and insulin act to suppress apoptosis in mammary epithelium. It has also become clear that adherent epithelial cells require interactions with the extracellular matrix for their survival. Indeed, interplay between these two types of extracellular survival factor occurs at the level of intracellular signal transduction. We shall show that the specialised ECM known as basement membrane controls the ability of insulin to deliver PI 3-kinase-regulated survival signals, and that this is mediated through the integrin class of receptors.

Commitment to mammary apoptosis in vivo is regulated through a wide spectrum of Bcl-2 family proteins, including Bcl-x, Bcl-w, Bax, Bak, and Bad. Part of the control of apoptosis comes from the developmental regulation of gene expression in this family, since transcription of Bcl-w, Bak and Bad is altered as cells enter post-lactational involution. In addition, cell-autonomous regulation of apoptosis in the absence of protein synthesis is also a key player, and the cell death protein Bax regulates apoptosis through its subcellular localisation. In healthy cells Bax is cytoplasmic, but altered survival signalling promotes translocation to mitochondria: we now know that the ECM has a critical role in regulating Bax distribution, and that this occurs through protein tyrosine kinase signal-transduction pathways.