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1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Rm. 8009, Omaha, NE 68198-6805, USA
2 Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg. 10, Room 8B07, 9000 Rockville Pike, Bethesda, MD 20892-1750, USA
3 Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bldg. 8, Rm. 107, Bethesda, MD 20892-0822, USA
*Authors for correspondence (e-mail: kuwagner{at}unmc.edu and gs4d{at}nih.gov)
Accepted 18 December 2001
Mammary gland biologists have long assumed that differentiated secretory epithelial cells undergo programmed cell death at the end of lactation and that the alveolar compartment is reconstituted from undifferentiated precursor cells in subsequent pregnancies. It is generally agreed that the remodeled gland in a parous animal resembles that of a mature virgin at the morphological level. However, several physiological differences have been noted in comparing the responses of mammary epithelia from nulliparous versus parous females to hormonal stimulation and carcinogenic agents. We present genetic evidence that an involuted mammary gland is fundamentally different from a virgin gland, despite its close morphological resemblance. This difference results from the formation of a new mammary epithelial cell population that originates from differentiating cells during pregnancy. In contrast to the majority of fully committed alveolar cells, this epithelial population does not undergo cell death during involution or remodeling after lactation. We show that these cells can function as alveolar progenitors in subsequent pregnancies and that they can play an important role in functional adaptation in genetically engineered mice, which exhibit a reversion of a lactation-deficient phenotype in multiparous animals. In transplantation studies, this parity-induced epithelial population shows the capacity for self-renewal and contributes significantly to the reconstitution of the resulting mammary outgrowth (i.e. ductal morphogenesis and lobulogenesis). We propose that this parity-induced population contributes importantly to the biological differences between the mammary glands of parous and nulliparous females.
Key words: Mammary gland, Cre recombinase, Epithelium, Parity, Stem cells, Involution, Differentiation, Mouse
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