Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution

Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution

^*Division of Infectious Diseases, Department of Medicine, University of Maryland Medical School, Baltimore Veterans Affairs Medical Center, and Institute of Human Virology, Baltimore, MD 21201; ^†Laboratory of Biochemistry and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20815; ^‡Laboratory of Cell Biology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20815; and ^§Department of Physiology, University of Maryland Medical School, Baltimore, MD 21201

Abstract

Programmed cell death (PCD) of mammary alveolar cells during involution commences within hours of the end of suckling. Locally, milk accumulates within alveolar lumens; systemically, levels of lactogenic hormones fall. Four experimental models were used to define the role of local factors as compared with systemic hormones during the first and second stages of involution. In three models, milk release was disrupted in the presence of systemic lactogenic hormones: (i) sealing of the teats, (ii) mammary gland transplants that cannot release milk due to the absence of a teat connection, and (iii) inactivation of the oxytocin gene. The ability of systemic hormones to preserve lobular-alveolar structure without blocking PCD was illustrated using a fourth transgenic model of lactation failure. During the first stage of involution, local signals were sufficient to induce alveolar PCD even in the presence of systemic lactogenic hormones. PCD coincided with bax induction, decreased expression of milk proteins, block of prolactin signal transduction through Stat5a and 5b, and activation of Stat3. The two stages of mammary gland involution are regulated by progressive gain of death signals and loss of survival factors. This study demonstrates that genetic events that occur during the first reversible stage are controlled by local factors. These mammary-derived death signals are dominant over protective effects related to systemic hormone stimulation.

Footnotes

↵ ¶ To whom reprint requests should be addressed at: University of Maryland Medical School, Room 545, Medical Biotechnology Center, 725 West Lombard Street, Baltimore, MD 21201. e-mail: furth{at}nih.gov.
Ruth Sager, Dana–Farber Cancer Institute, Boston, MA
ABBREVIATIONS:

PCD,

programmed cell death;

WAP,

whey acidic protein;

TAg,

simian virus 40 T antigen;

ECM,

extracellular matrix;

Ab,

antibody