p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis.
In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63+/- glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63+/- glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63+/- mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa(LSL-LacZ);WAP-Cre transgenics (LSL-LacZ, lox-stop-lox β-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63+/- glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63+/- ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63+/+ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.
Department of Pathology, Stony Brook University, School of Medicine, Stony Brook, NY 11794, USA.
A R
AR
Yallowitz
Department of Pathology, Stony Brook University, School of Medicine, Stony Brook, NY 11794, USA.
E M
EM
Alexandrova
Department of Pathology, Stony Brook University, School of Medicine, Stony Brook, NY 11794, USA.
F
F
Talos
Department of Pathology, Stony Brook University, School of Medicine, Stony Brook, NY 11794, USA.
S
S
Xu
Department of Pathology, Stony Brook University, School of Medicine, Stony Brook, NY 11794, USA.
N D
ND
Marchenko
Department of Pathology, Stony Brook University, School of Medicine, Stony Brook, NY 11794, USA.
U M
UM
Moll
D000818:Animals; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D010750:Phosphoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C524056:Erbb2 protein, mouse