Development of mammary tumors by conditional expression of GLI1.

A diverse set of cellular defects, presumably elicited by multiple genetic alterations, underlies cancer development. Aberrant Hedgehog (Hh) signaling has recently been implicated in the development and maintenance of breast cancer. However, evidence conclusively showing that activated Hh signaling can induce mammary tumors is lacking. We now show that transgenic expression of the Hh effector protein GLI1 under the regulation of the mouse mammary tumor virus promoter, expressed in the mouse mammary gland, is associated with the appearance of hyperplastic lesions, defective terminal end buds, and tumor development. The GLI1-induced tumors are histologically heterogeneous and involve the expansion of a population of epithelial cells expressing the progenitor cell markers keratin 6 and Bmi-1. Moreover, tumor cells express genes involved in proliferation, cell survival, and metastasis. GLI1-induced tumors do not fully regress following transgene deinduction, indicating that some tumors develop and are maintained autonomously, independent of sustained transgenic GLI1 expression. The data strongly support a role of Hh/GLI signaling in breast cancer development and suggest that inhibition of this signaling pathway represents a new therapeutic opportunity for limiting tumorigenesis and early tumorigenic progression.

[1]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[2]  Hua Li,et al.  Reciprocal Intraepithelial Interactions Between TP63 and Hedgehog Signaling Regulate Quiescence and Activation of Progenitor Elaboration by Mammary Stem Cells , 2008, Stem cells.

[3]  K. Horwitz,et al.  Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts , 2008, Proceedings of the National Academy of Sciences.

[4]  H. Varmus,et al.  Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras , 2008, Proceedings of the National Academy of Sciences.

[5]  S. Merajver,et al.  BRCA1 regulates human mammary stem/progenitor cell fate , 2008, Proceedings of the National Academy of Sciences.

[6]  Stephen J. Elledge,et al.  Profiling Essential Genes in Human Mammary Cells by Multiplex RNAi Screening , 2008, Science.

[7]  L. Montanaro,et al.  The basal‐like breast carcinoma phenotype is regulated by SLUG gene expression , 2008, The Journal of pathology.

[8]  M. Kleman,et al.  Targeted Expression of GLI1 in the Mammary Gland Disrupts Pregnancy-induced Maturation and Causes Lactation Failure* , 2007, Journal of Biological Chemistry.

[9]  M. Lauth,et al.  Non-Canonical Activation of GLI Transcription Factors: Implications for Targeted Anti-Cancer Therapy , 2007, Cell cycle.

[10]  R. Weinberg,et al.  Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes. , 2007, Cancer cell.

[11]  Alicia Zhou,et al.  Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers , 2007, Proceedings of the National Academy of Sciences.

[12]  T. Shimokawa,et al.  Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists , 2007, Proceedings of the National Academy of Sciences.

[13]  S. Hilsenbeck,et al.  Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia , 2007, Development.

[14]  R. Beroukhim,et al.  Molecular definition of breast tumor heterogeneity. , 2007, Cancer cell.

[15]  H. Phillip Koeffler,et al.  Unmasking of epigenetically silenced genes reveals DNA promoter methylation and reduced expression of PTCH in breast cancer , 2007, Breast Cancer Research and Treatment.

[16]  Lee L. Rubin,et al.  Targeting the Hedgehog pathway in cancer , 2006, Nature Reviews Drug Discovery.

[17]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[18]  P. Cowin,et al.  Gli3-mediated repression of Hedgehog targets is required for normal mammary development , 2006, Development.

[19]  G. Dontu,et al.  Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. , 2006, Cancer research.

[20]  G. Page,et al.  Hedgehog signaling and response to cyclopamine differs in epithelial and stromal cells in benign breast and breast cancer , 2006, Cancer biology & therapy.

[21]  M. Kraus,et al.  Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation , 2006, Oncogene.

[22]  Joel Greshock,et al.  High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization , 2005, Breast Cancer Research.

[23]  P. A. Pérez-Mancera,et al.  Cancer development induced by graded expression of Snail in mice. , 2005, Human molecular genetics.

[24]  Robert D Cardiff,et al.  The transcriptional repressor Snail promotes mammary tumor recurrence. , 2005, Cancer cell.

[25]  A. Howell,et al.  A putative human breast stem cell population is enriched for steroid receptor-positive cells. , 2005, Developmental biology.

[26]  P. Lichter,et al.  Candidate genes in breast cancer revealed by microarray-based comparative genomic hybridization of archived tissue. , 2005, Cancer research.

[27]  Robert B Boxer,et al.  Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. , 2004, Cancer cell.

[28]  E. Crivellato,et al.  Mast cell contribution to angiogenesis related to tumour progression , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[29]  G. Hortobagyi,et al.  Prognostic molecular markers in early breast cancer , 2004, Breast Cancer Research.

[30]  H. Varmus,et al.  Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  L. Cornelius,et al.  Matrix metalloproteinases: pro- and anti-angiogenic activities. , 2000, The journal of investigative dermatology. Symposium proceedings.

[33]  C. Sugnet,et al.  Defects in mouse mammary gland development caused by conditional haploinsufficiency of Patched-1. , 1999, Development.

[34]  D. Roop,et al.  Differential keratin gene expression in developing, differentiating, preneoplastic, and neoplastic mouse mammary epithelium. , 1990, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[35]  C. Eaves,et al.  Epithelial Progenitors in the Normal Human Mammary Gland , 2005, Journal of Mammary Gland Biology and Neoplasia.