Cyclin D1-dependent induction of luminal inflammatory breast tumors by activated notch3.
Accumulating evidence suggests that Notch3 (N3) is involved in breast cancer development, but its precise contributions are not well understood. Here, we report that pregnant mice expressing an activated intracellular form of N3 (N3(IC)) exhibit a cyclin D1-dependent expansion of premalignant CD24(+) CD29(low) luminal progenitors with enhanced differentiation potential in vitro and in vivo. Parous mice developed luminal mammary tumors in a cyclin D1-dependent manner. Notably, mice expressing higher levels of N3(IC) exhibited tumors resembling inflammatory breast cancer that frequently metastasized. N3(IC)-induced tumors contained a large percentage of tumor-initiating cells, but these were reduced significantly in tumors derived from N3(IC) transgenic mice that were heterozygous for cyclin D1. After transplantation in the presence of normal mammary cells, N3(IC)-expressing tumor cells became less malignant, differentiating into CK6(+) CK18(+) CK5(-) alveolar-like structures akin to expanded luminal progenitors from which they were likely derived. Taken together, our results argue that activated N3 signaling primarily affects luminal progenitors among mammary cell subsets, with more pronounced levels of activation influencing tumor type, and provide a novel model of inflammatory breast cancer.
Authors' Affiliations: Laboratory of Molecular Biology, Clinical Research Institute of Montreal; Department of Microbiology and Immunology Université de Montréal; and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
Hua
H
Ling
Jean-René
JR
Sylvestre
Paul
P
Jolicoeur
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D051927:CD24 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
D051927:CD24 Antigen; C530105:Ccnd1 protein, mouse; C499373:Notch3 protein, mouse; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D019938:Cyclin D1