Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis.

Transforming growth factor-beta (TGF-beta) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-beta signaling in mammary tumorigenesis is complex, as TGF-beta has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-beta signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-beta receptor, Tgfbr2, was conditionally deleted in the mammary epithelium (Tgfbr2MGKO). Loss of Tgfbr2 in the mammary epithelium results in lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Tgfbr2MGKO mice were mated to the mouse mammary tumor virus-polyomavirus middle T antigen (PyVmT) transgenic mouse model of metastatic breast cancer. Loss of Tgfbr2 in the context of PyVmT expression results in a shortened median tumor latency and an increased formation of pulmonary metastases. Thus, our studies support a tumor-suppressive role for epithelial TGF-beta signaling in mammary gland tumorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-beta signaling in the carcinoma cells.

[1]  W. Muller,et al.  Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. , 2004, Cancer cell.

[2]  Shiva Gautam,et al.  Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. , 2004, Cancer Research.

[3]  K. Tanabe,et al.  The role of Fas ligand and transforming growth factor β in tumor progression , 2004 .

[4]  Luzhe Sun.  Tumor-suppressive and promoting function of transforming growth factor beta. , 2004, Frontiers in bioscience : a journal and virtual library.

[5]  Y. Shyr,et al.  Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. , 2003, The American journal of pathology.

[6]  R. Roberts,et al.  The loss of TGF-beta signaling promotes prostate cancer metastasis. , 2003, Neoplasia.

[7]  L. Wakefield,et al.  Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. , 2002, The Journal of clinical investigation.

[8]  C. Arteaga,et al.  Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases , 2002 .

[9]  L. Wakefield,et al.  TGF-β signaling: positive and negative effects on tumorigenesis , 2002 .

[10]  H. Moses,et al.  Conditional inactivation of the TGF‐β type II receptor using Cre:Lox , 2002, Genesis.

[11]  L. Hennighausen,et al.  Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice , 2001, Transgenic research.

[12]  R. Derynck,et al.  TGF-β signaling in cancer – a double-edged sword , 2001 .

[13]  R. Flavell,et al.  Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells , 2001, Nature Medicine.

[14]  P J Catalano,et al.  Molecular predictors of survival after adjuvant chemotherapy for colon cancer. , 2001, The New England journal of medicine.

[15]  M. Rudnicki,et al.  Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Carlos L Arteaga,et al.  Transforming growth factor-β and breast cancer: Tumor promoting effects of transforming growth factor-β , 2000, Breast Cancer Research.

[17]  Simpson,et al.  Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in‐situ and invasive carcinomas , 2000, Histopathology.

[18]  W. Dupont,et al.  Transforming Growth Factor-β and Breast Cancer Risk in Women With Mammary Epithelial Hyperplasia. , 1999, Journal of the National Cancer Institute.

[19]  H. Moses,et al.  Overexpression of a kinase-deficient transforming growth factor-beta type II receptor in mouse mammary stroma results in increased epithelial branching. , 1999, Molecular biology of the cell.

[20]  H. Moses,et al.  Inhibition of DNA Synthesis by a Farnesyltransferase Inhibitor Involves Inhibition of the p70s6k Pathway* , 1999, The Journal of Biological Chemistry.

[21]  L. Myeroff,et al.  Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. , 1998, Cancer research.

[22]  Y. Nagamachi,et al.  Absence of mutations in the analysis of coding sequences of the entire transforming growth factor-beta type II receptor gene in sporadic human breast cancers. , 1998, Oncology reports.

[23]  R. Derynck,et al.  Dominant-negative interference of the transforming growth factor beta type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[24]  L. Wakefield,et al.  Transgenic Mice Overexpressing a Dominant-negative Mutant Type II Transforming Growth Factor β Receptor Show Enhanced Tumorigenesis in the Mammary Gland and Lung in Response to the Carcinogen 7,12-Dimethylbenz-[a]-anthracene , 1997 .

[25]  S. Yuspa,et al.  Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. , 1996, Cancer research.

[26]  R. Coffey,et al.  Mammary tumor suppression by transforming growth factor beta 1 transgene expression. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  H. Moses,et al.  TGF‐β regulation of epithelial cell proliferation , 1992, Molecular reproduction and development.

[28]  R. Cardiff,et al.  Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease , 1992, Molecular and cellular biology.

[29]  K. Tanabe,et al.  The role of Fas ligand and transforming growth factor beta in tumor progression: molecular mechanisms of immune privilege via Fas-mediated apoptosis and potential targets for cancer therapy. , 2004, Cancer.

[30]  R. Flavell,et al.  Transforming growth factor-beta in T-cell biology. , 2002, Nature reviews. Immunology.

[31]  R. Derynck,et al.  TGF-beta signaling in cancer--a double-edged sword. , 2001, Trends in cell biology.

[32]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[33]  H. Moses,et al.  Inhibition of DNA synthesis by a farnesyltransferase inhibitor involves inhibition of the p70(s6k) pathway. , 1999, The Journal of biological chemistry.

[34]  C. Arteaga,et al.  Transforming Growth Factor-β and Breast Cancer , 1999 .