**1. Introduction**

Upon weaning, the mammary gland recovers a morphology similar to its prepregnant state through an intricate process known as postlactational involution. During this phase, a high proportion of epithelial cells die, the basal membrane is partially digested, and the adipose tissue reoccupies the space left by the regressed alveoli. In the mouse, mammary gland involution has been described as a two-step process according to its reversibility [1]. The first reversible phase is induced by *local factors* and lasts approximately 48 h during which it can be reversed through resuckling. At this stage, proapoptotic factors are upregulated, while survival factors

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are reduced. This reversible phase is followed after 72 h by a nonreversible phase where widespread apoptosis and tissue remodeling takes place. This later phase requires *systemic factors and local* proteases such as MMP-3/Stromelysin-1 and MMP11/Stromelysin-3, MMP2/Gelatinase A, ICE (interleukin-1 beta converting enzyme), and Urokinase-type plasminogen activator [2].

In 1997, Li et al. [3] defined the role of local factors as compared with systemic hormones during the first and second stages of involution. When milk release was disrupted in the presence of systemic lactogenic hormones, they demonstrated that local signals were sufficient to induce alveolar cell death. These authors demonstrated that a variety of procedures successfully triggered mammary involution, although none of them prevented the presence of circulating lactogenic hormones. For example, sealing of the teats, mammary gland transplants unable to release milk due to the absence of a teat connection or inactivation of the oxytocin gene efficiently induced mammary cell death. On the other hand, in these scenarios, systemic hormones were able to preserve lobular-alveolar structure, although they did not prevent apoptosis. This chapter reviews the discovery of the local factors involved in the process of involution as well as the finding of the mechanisms involved in their ability to induce cell death shortly after weaning. In addition, the generation of a pro-oncogenic microenvironment during mammary involution, which is able to facilitate breast cancer progression, is also discussed.
