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Uncoupling of PI3K from ErbB3 impairs mammary gland development but does not impact on ErbB2-induced mammary tumorigenesis

Item Type:Article
Title:Uncoupling of PI3K from ErbB3 impairs mammary gland development but does not impact on ErbB2-induced mammary tumorigenesis
Creators Name:Lahlou, H. and Mueller, T. and Sanguin-Gendreau, V. and Birchmeier, C. and Muller, W.J.
Abstract:The formation of ErbB2/ErbB3 heterodimers plays a critical role in ErbB2-mediated signaling in both normal mammary development and mammary tumor progression. Through 7 phosphoinositide 3-kinase (PI3K) phosphotyrosine-binding sites, ErbB3 is able to recruit PI3K and initiate the PI3K/AKT signaling pathway. To directly explore the importance of the ErbB3/PI3K pathway in mammary development and tumorigenesis, we generated a mouse model that carries a mutant ErbB3 allele lacking the seven known PI3K-binding sites (ErbB3(Δ85)). Mice homozygous for the ErbB3(Δ85) allele exhibited an initial early growth defect and a dramatic impairment of mammary epithelial outgrowth. Although homozygous adult mice eventually recovered from the growth defect, their mammary glands continued to manifest the mammary outgrowth and lactation defects throughout their adult life. Interestingly, despite the presence of a profound mammary gland defect, all of the female ErbB3Δ85 mice developed metastatic ErbB2-induced mammary tumors secondary to mammary epithelial expression of an activated ErbB2 oncogene capable of compensatory PI3K signaling from both EGF receptor and ErbB2. Our findings therefore indicate that, although ErbB3-associated PI3K activity is critical for mammary development, it is dispensable for ErbB2-induced mammary tumor progression.
Keywords:Animal Mammary Glands, Animal Mammary Neoplasms, Apoptosis, erbB-2 Receptor, erbB-3 Receptor, Lactation, Neoplastic Cell Transformation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction, Transgenic Mice, Animals, Mice
Source:Cancer Research
Publisher:American Association for Cancer Research
Page Range:3080-3090
Date:15 June 2012
Official Publication:https://doi.org/10.1158/0008-5472.CAN-11-3513
PubMed:View item in PubMed

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