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1.
Cell Death Differ ; 17(10): 1600-12, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20379195

ABSTRACT

The breast epithelium has two major compartments, luminal and basal cells, that are established and maintained by poorly understood mechanisms. The p53 homolog, p63, is required for the formation of mammary buds, but its function in the breast after birth is unknown. We show that in primary human breast epithelial cells, maintenance of basal cell characteristics depends on continued expression of the p63 isoform, ΔNp63, which is expressed in the basal compartment. Forced expression of ΔNp63 in purified luminal cells confers a basal phenotype. Notch signaling downmodulates ΔNp63 expression and mimics ΔNp63 depletion, whereas forced expression of ΔNp63 partially counteracts the effects of Notch. Consistent with Notch activation specifying luminal cell fate in the mammary gland, Notch signaling activity is specifically detected in mice at sites of pubertal ductal morphogenesis where luminal cell fate is determined. Basal cells in which Notch signaling is active show decreased p63 expression. Both constitutive expression of ΔNp63 and ablation of Notch signaling are incompatible with luminal cell fate. Thus, the balance between basal and luminal cell compartments of the breast is regulated by antagonistic functions of ΔNp63 and Notch.


Subject(s)
Epithelial Cells/cytology , Mammary Glands, Human/cytology , Phosphoproteins/physiology , Receptor, Notch1/metabolism , Trans-Activators/physiology , Tumor Suppressor Proteins/physiology , Animals , Apoptosis , Female , Humans , Mammary Glands, Animal/cytology , Mice , Mice, Transgenic , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/metabolism , Receptor, Notch1/antagonists & inhibitors , Receptor, Notch1/physiology , Signal Transduction , Trans-Activators/antagonists & inhibitors , Trans-Activators/metabolism , Transcription Factors , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/metabolism
2.
Genes Dev ; 14(6): 650-4, 2000 Mar 15.
Article in English | MEDLINE | ID: mdl-10733525

ABSTRACT

Female reproductive hormones control mammary gland morphogenesis. In the absence of the progesterone receptor (PR) from the mammary epithelium, ductal side-branching fails to occur. We can overcome this defect by ectopic expression of the protooncogene Wnt-1. Transplantation of mammary epithelia from Wnt-4(-)/(-) mice shows that Wnt-4 has an essential role in side-branching early in pregnancy. PR and Wnt-4 mRNAs colocalize to the luminal compartment of the ductal epithelium. Progesterone induces Wnt-4 in mammary epithelial cells and is required for increased Wnt-4 expression during pregnancy. Thus, Wnt signaling is essential in mediating progesterone function during mammary gland morphogenesis.


Subject(s)
Mammary Glands, Animal/embryology , Progesterone/metabolism , Proto-Oncogene Proteins/genetics , Signal Transduction , Animals , Base Sequence , DNA Primers , Female , Gene Expression Regulation, Developmental , In Situ Hybridization , Mice , Mice, Knockout , RNA Probes , Receptors, Progesterone/genetics , Wnt Proteins , Wnt4 Protein
3.
Dev Biol ; 210(1): 96-106, 1999 Jun 01.
Article in English | MEDLINE | ID: mdl-10364430

ABSTRACT

The inactivation of the prolactin receptor gene by homologous recombination has made it possible to investigate the role of prolactin signaling in mammary gland development without resort to ablative surgery of the endocrine glands. In knockout mice lacking the prolactin receptor, mammary development is normal up to puberty. Subsequently, the ducts branch less frequently than those of wild-type animals. While terminal end buds differentiate to alveolar buds in wild-type females by the end of puberty, in knockout females terminal end bud-like structures persist at the ductal ends. To distinguish between the developmental defects that are intrinsic to the epithelium and those that result from systemic endocrine alterations in prolactin receptor knockout mice, mammary epithelium from prolactin receptor knockouts was transplanted into mammary fat pads of wild-type mice. In virgin mice, the knockout epithelial transplants developed normally at puberty, indicating an indirect effect of prolactin on ductal development. Prolactin receptor knockout females are infertile due to multiple reproductive defects, but epithelial transplants allowed us to assess the extent to which the absence of prolactin receptor is limiting, under systemic conditions that allow full mammary gland development. During pregnancy, the prolactin receptor knockout transplants showed normal side branching and the formation of alveolar buds, but no lobuloalveolar development. Thus, prolactin affects mammary morphogenesis in two different ways: it controls ductal side branching and terminal end bud regression in virgin animals via indirect mechanisms, but acts directly on the mammary epithelium to produce lobuloalveolar development during pregnancy.


Subject(s)
Mammary Glands, Animal/growth & development , Prolactin/pharmacology , Receptors, Prolactin/drug effects , Animals , Female , Gene Expression Regulation, Developmental , Heterozygote , Histocytochemistry , Mammary Glands, Animal/drug effects , Mice , Mice, Knockout , Pregnancy , Signal Transduction , Tissue Transplantation
4.
Proc Natl Acad Sci U S A ; 95(9): 5076-81, 1998 Apr 28.
Article in English | MEDLINE | ID: mdl-9560231

ABSTRACT

Recently generated progesterone receptor (PR)-negative (PR-/-) mice provide an excellent model for dissecting the role of progesterone in the development of the mammary gland during puberty and pregnancy. However, the full extent of the mammary gland defect in these mice caused by the absence of the PR cannot be assessed, because PR-/- mice do not exhibit estrous cycles and fail to become pregnant. To circumvent this difficulty, we have transplanted PR-/- breasts into wild-type mice, and we have demonstrated that the development of the mammary gland in the absence of the PR is arrested at the stage of the simple ductal system found in the young virgin mouse. Mammary transplants lacking the PR in the stromal compartment give rise to normal alveolar growth, whereas transplants containing PR-/- epithelium conserve the abnormal phenotype. Chimeric epithelia in which PR-/- cells are in close vicinity to PR wild-type cells go through complete alveolar development to which the PR-/- cells contribute. Together, these results indicate that progesterone acts by a paracrine mechanism on a subset of mammary epithelial cells to allow for alveolar growth and that expression of the PR is not required in all the cells of the mammary epithelium in order for alveolar development to proceed normally.


Subject(s)
Mammary Glands, Animal/growth & development , Receptors, Progesterone/physiology , Animals , Epithelium/growth & development , Female , Mammary Glands, Animal/cytology , Mammary Glands, Animal/transplantation , Mice , Mice, Knockout , Paracrine Communication , Pregnancy
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