Pestell Lab 

 

  • The Pestell laboratory was the first to demonstrate that specific target genes determine epithelial cancer stem cells (CSC) number using transgenic or inducible inactivation mice, including Akt1(1), NFkB(2), cyclin D1(3), p21CIP1(4), c-Jun(5), and Dach1(6).
  • The Pestell laboratory defined distinct roles for cyclin D1 in polarity vs stem cell function(7).
  • Using a ponasterone-regulated IkB super-repressor, our laboratory was the first to show that NFkB governs both the onset and progression of ErbB2 mammary tumorigenesis and this functions in part through the expansion of mammary cancer stem cells(2,8).
  • We showed endogenous c-Jun(5,9) and endogenous NFkB(2,8) enhance mammary CSC number.
  • We showed p21Cip1(4) and Dach1(6) restrain CSC number.  
  • We have defined the function of Dach1 in cell fate and as a candidate tumor suppressor https://en.wikipedia.org/wiki/DACH1 
  • We showed that the cyclin D1 gene is a target of the key stem cell regulatory factor Notch, in Pofut1-/- mouse embryos, in embryos with an inactivating mutation in Notch1(10) and Notch1-mediated transformation was dependent on cyclin D1(10).
  • We showed mammary gland targeted β-cateninmut induced mammary adenocarcinoma with increased cyclin D1 levels(11). These studies extended our molecular analysis of β-catenin and cyclin D1 studies in breast cancer(12-14).
  • We generated transgenic mice that regulate temporal and spatial control of activated Notch1 targeted to the mammary gland (Inducible Notch1IC) and developed mice in which endogenous Notch1 can be deleted from the mammary gland (Notch1fl/fl, MMTV-Cre)(15). Using floxed Notch (Notch1fl/fl) mice we showed ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1 and the induction occurred via cyclin D1(15).
  • We recently define the role of the G protein coupled receptor CCR5 as a cancer stem cell marker.




1. Ju X, Katiyar S, Wang C, Liu M, Jiao X, Li S, et al. Akt1 governs breast cancer progression in vivo. Proc Natl Acad Sci USA 2007;104:7438-43
2. Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, et al. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res 2010;70:10464-73
3. Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, et al. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Molecular and Cellular Biology 2000;20:672-83
4. Liu M, Casimiro MC, Wang C, Shirley LA, Jiao X, Katiyar S, et al. p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci U S A 2009;106:19035-9
5. Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, et al. c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem 2010;285:8218-26
6. Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, et al. Cell fate determination factor Dachshund reprograms breast cancer stem cell function. J Biol Chem 2011;286:2132-42
7. Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, et al. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell 2009;139:679-92
8. Liu M, Ju X, Willmarth NE, Casimiro MC, Ojeifo J, Sakamaki T, et al. Nuclear factor-kappaB enhances ErbB2-induced mammary tumorigenesis and neoangiogenesis in vivo. Am J Pathol 2009;174:1910-20
9. Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, et al. C-jun inhibits mammary apoptosis in vivo. Mol Biol Cell 2010;21:4264-74
10. Stahl M, Ge, C., Shi, S., Pestell, R.G., and Stanley, P. Notch1-Induced transformation of RKE-1 cells requires upregulation of cyclin D1. Cancer Research 2006;15:7562-70
11. Imbert A, Eelkema R, Jordan S, Feiner H, Cowin P. DN89b-catenin induces precocious development, differentiation, and neoplasia in mammary gland. J Cell Biol 2001;153:555-68
12. Galbiati F, Volonte D, Engelman JA, Watanabe G, Burk R, Pestell RG, et al. Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and activate the p42/p44 MAP kinase cascade. EMBO J 1998;17:6633-48
13. Lin S-Y, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, et al. Beta-catenin, a novel prognostic marker for breast cancer: Its role in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA 2000;97:4262-6
14. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell RG, et al. The cyclin D1 gene is a target of the b-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 1999;96:5522-7
15. Lindsay J, Jiao X, Sakamaki T, Casimiro MC, Shirley LA, Tran TH, et al. ErbB2 induces Notch1 activity and function in breast cancer cells. Clin Transl Sci 2008;1:107-15Type your paragraph here.