Transforming growth factor beta 3 induces cell death during the first stage of mammary gland involution

Involution of the mammary gland following weaning is divided into two disti nct phases. Initially, milk stasis results in the induction of local factor s that cause apoptosis in the alveolar epithelium. Secondly after a prolong ed absence of suckling, the consequent decline in circulating lactogenic ho rmone concentrations initiates remodeling of the mammary gland to the virgi n-like state. We have shown that immediately following weaning TGF beta 3 m RNA and protein is rapidly induced in the mammary epithelium and that this precedes the onset of apoptosis. Unilateral inhibition of suckling and horm onal reconstitution experiments showed that TGF beta 3 induction is regulat ed by milk stasis and not by the circulating hormonal concentration. Direct ed expression of TGF beta 3 in the alveolar epithelium of lactating mice us ing a beta-lactoglobulin promoter mobilized SMAD4 translocation to the nucl eus and caused apoptosis of these cells, but not tissue remodeling. Transpl antation of neonatal mammary tissue derived from TGF beta 3 null mutant mic e into syngenic hosts resulted in a significant inhibition of cell death co mpared to wild-type mice upon milk stasis. These results provide direct evi dence that TGF beta 3 is a local mammary factor induced by milk stasis that causes apoptosis in the mammary gland epithelium during involution.