Perturbation of beta1-integrin function in involuting mammary gland results in premature dedifferentiation of secretory epithelial cells.
To study the mechanism of beta1-integrin function in vivo, we have generated transgenic mouse expressing a dominant negative mutant of beta1-integrin under the control of mouse mammary tumor virus (MMTV) promoter (MMTV-beta1-cyto). Mammary glands from MMTV-beta1-cyto transgenic females present significant growth defects during pregnancy and lactation and impaired differentiation of secretory epithelial cells at the onset of lactation. We report herein that perturbation of beta1-integrin function in involuting mammary gland induced precocious dedifferentiation of the secretory epithelium, as shown by the premature decrease in beta-casein and whey acidic protein mRNA levels, accompanied by inactivation of STAT5, a transcription factor essential for mammary gland development and up-regulation of nuclear factor-kappaB, a negative regulator of STAT5 signaling. This is the first study demonstrating in vivo that cell-extracellular matrix interactions involving beta1-integrins play an important role in the control of milk gene transcription and in the maintenance of the mammary epithelial cell differentiated state.
Faraldo
Marisa M
MM
Unité Mixte Recherche 144, Centre National de la Recherche Scientifique-Institut Curie, Section de Recherche, 75248 Paris, France.
Deugnier
Marie-Ange
MA
Tlouzeau
Sylvie
S
Thiery
Jean Paul
JP
Glukhova
Marina A
MA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D017930:Genes, Reporter; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2; D007774:Lactation / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D019012:Integrin beta1; D008894:Milk Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2