Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis.

Metastatic disease is the primary cause of death in breast cancer, the most common malignancy in Western women. Loss of E-cadherin is associated with tumor metastasis, as well as with invasive lobular carcinoma (ILC), which accounts for 10%-15% of all breast cancers. To study the role of E-cadherin in breast oncogenesis, we have introduced conditional E-cadherin mutations into a mouse tumor model based on epithelium-specific knockout of p53. Combined loss of E-cadherin and p53 resulted in accelerated development of invasive and metastatic mammary carcinomas, which show strong resemblance to human ILC. Moreover, loss of E-cadherin induced anoikis resistance and facilitated angiogenesis, thus promoting metastatic disease. Our results suggest that loss of E-cadherin contributes to both mammary tumor initiation and metastasis.

[1]  A. G. Herreros,et al.  The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells , 2000, Nature Cell Biology.

[2]  R. Guzman,et al.  Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. J. van de Vijver,et al.  © 1997 Cancer Research Campaign , 2022 .

[4]  A. Bradley,et al.  Induced mitotic recombination: a switch in time , 2002, Nature Genetics.

[5]  W. Crocker,et al.  Polarity , 1910, Botanical Gazette.

[6]  J. Thiery.  Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[7]  D. Drubin,et al.  Origins of Cell Polarity , 1996, Cell.

[8]  H. Pasolli,et al.  Conditional targeting of E-cadherin in skin: insights into hyperproliferative and degenerative responses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  W. Fiers,et al.  Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role , 1991, Cell.

[10]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[11]  P. Devilee,et al.  At least two different regions are involved in allelic imbalance on chromosome arm 16q in breast cancer , 1994, Genes, chromosomes & cancer.

[12]  L. Norton,et al.  p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  R. Bende,et al.  The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma , 2003, Leukemia.

[14]  Haiyan I. Li,et al.  Purification and unique properties of mammary epithelial stem cells , 2006, Nature.

[15]  A. Berns,et al.  Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer , 2001, Nature Genetics.

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

[17]  Kenneth M. Yamada,et al.  The Zinc-finger Protein Slug Causes Desmosome Dissociation, an Initial and Necessary Step for Growth Factor–induced Epithelial–mesenchymal Transition , 1997 .

[18]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[19]  Avri Ben-Ze'ev,et al.  The cadherin-catenin adhesion system in signaling and cancer. , 2002, The Journal of clinical investigation.

[20]  Jane Fridlyand,et al.  Differentiation of lobular versus ductal breast carcinomas by expression microarray analysis. , 2003, Cancer research.

[21]  Heinz Höfler,et al.  Mutations of the human E‐cadherin (CDH1) gene , 1998, Human mutation.

[22]  S. Hirohashi,et al.  Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  S. Hirohashi,et al.  E-cadherin gene mutations in human gastric carcinoma cell lines. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[24]  U. Suter,et al.  E‐cadherin controls adherens junctions in the epidermis and the renewal of hair follicles , 2003, The EMBO journal.

[25]  H. Schwarz,et al.  E‐cadherin is essential for in vivo epidermal barrier function by regulating tight junctions , 2005, The EMBO journal.

[26]  S. Wellings,et al.  Development of human breast cancer. , 1980, Advances in cancer research.

[27]  René Bernards,et al.  A progression puzzle. , 2002, Nature.

[28]  François Vaillant,et al.  Generation of a functional mammary gland from a single stem cell , 2006, Nature.

[29]  Elaine Fuchs,et al.  Sticky Business Orchestrating Cellular Signals at Adherens Junctions , 2003, Cell.

[30]  J. Herman,et al.  E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. , 1995, Cancer research.

[31]  R. Elledge,et al.  Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome , 2004, Breast Cancer Research.

[32]  Fred H. Gage,et al.  Development of a Self-Inactivating Lentivirus Vector , 1998, Journal of Virology.

[33]  Roland Eils,et al.  High-Resolution Genomic Profiling Reveals Association of Chromosomal Aberrations on 1q and 16p with Histologic and Genetic Subgroups of Invasive Breast Cancer , 2006, Clinical Cancer Research.

[34]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[35]  B. Blom,et al.  Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2-/- gammac-/- mice: functional inactivation of p53 in developing T cells. , 2004, Blood.

[36]  Gerhard Christofori,et al.  Cell adhesion and signalling by cadherins and Ig-CAMs in cancer , 2004, Nature Reviews Cancer.

[37]  R. Soslow,et al.  A comparison of cell cycle markers in well-differentiated lobular and ductal carcinomas , 2000, Breast Cancer Research and Treatment.

[38]  A. Berns,et al.  p107 is a suppressor of retinoblastoma development in pRb-deficient mice. , 1998, Genes & development.

[39]  G. Berx,et al.  The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression , 2001, Breast Cancer Research.

[40]  Francisco Portillo,et al.  The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression , 2000, Nature Cell Biology.

[41]  A. Marchetti,et al.  p53 Mutations and Histologie Type of Invasive Breast Carcinoma , 1993, Cancer research.

[42]  P. O’Connell,et al.  Biomarker profile and genetic abnormalities in lobular carcinoma in situ , 2005, Breast Cancer Research and Treatment.

[43]  H M Jensen,et al.  An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. , 1975, Journal of the National Cancer Institute.

[44]  R. Kemler,et al.  E-cadherin is a survival factor for the lactating mouse mammary gland , 2002, Mechanisms of Development.

[45]  Carlos S. Moreno,et al.  MTA3, a Mi-2/NuRD Complex Subunit, Regulates an Invasive Growth Pathway in Breast Cancer , 2003, Cell.

[46]  G. Berx,et al.  The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. , 2001, Molecular cell.

[47]  M. Vijver,et al.  E‐cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. , 1995, The EMBO journal.

[48]  L. Brinton,et al.  Global trends in breast cancer incidence and mortality 1973-1997. , 2005, International journal of epidemiology.

[49]  David Botstein,et al.  Different gene expression patterns in invasive lobular and ductal carcinomas of the breast. , 2004, Molecular biology of the cell.

[50]  E. Fearon,et al.  The SLUG zinc-finger protein represses E-cadherin in breast cancer. , 2002, Cancer research.

[51]  M. Takeichi.  Morphogenetic roles of classic cadherins. , 1995, Current opinion in cell biology.

[52]  A. Gown,et al.  Cytokeratin 8 immunostaining pattern and E-cadherin expression distinguish lobular from ductal breast carcinoma. , 2000, American journal of clinical pathology.

[53]  D. Coradini,et al.  Infiltrating ductal and lobular breast carcinomas are characterised by different interrelationships among markers related to angiogenesis and hormone dependence , 2002, British Journal of Cancer.

[54]  S. Lakhani,et al.  The diagnosis and management of pre-invasive breast disease: Pathology of atypical lobular hyperplasia and lobular carcinoma in situ , 2003, Breast Cancer Research.

[55]  S. Ramaswamy,et al.  Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis , 2004, Cell.

[56]  D. Trono,et al.  A Third-Generation Lentivirus Vector with a Conditional Packaging System , 1998, Journal of Virology.

[57]  W. Birchmeier,et al.  E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells , 1991, The Journal of cell biology.

[58]  Alan Ashworth,et al.  Stem cells and breast cancer: A field in transit , 2003, Nature Reviews Cancer.

[59]  W. Birchmeier,et al.  E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton , 1994, The Journal of cell biology.