A mouse model of human breast cancer metastasis to human bone.

Currently, an in vivo model of human breast cancer metastasizing from the orthotopic site to bone does not exist, making it difficult to study the many steps of skeletal metastasis. Moreover, models used to identify the mechanisms by which breast cancer metastasizes to bone are limited to intracardiac injection, which seeds the cancer cells directly into the circulation, thus bypassing the early steps in the metastatic process. Such models do not reflect the full process of metastasis occurring in patients. We have developed an animal model of breast cancer metastasis in which the breast cancer cells and the bone target of osteotropic metastasis are both of human origin. The engrafted human bone is functional, based on finding human IgG in the mouse bloodstream, human B cells in the mouse spleen, and normal bone histology. Furthermore, orthotopic injection of a specific human breast cancer cell line, SUM1315 (derived from a metastatic nodule in a patient), later resulted in both bone and lung metastases. In the case of bone, metastasis was to the human implant and not the mouse skeleton, indicating a species-specific osteotropism. This model replicates the events observed in patients with breast cancer skeletal metastases and serves as a useful and relevant model for studying the disease.

[1]  R. Coleman.  Future Directions in the Treatment and Prevention of Bone Metastases , 2002, American journal of clinical oncology.

[2]  T. Martin,et al.  A novel orthotopic model of breast cancer metastasis to bone , 1999, Clinical & Experimental Metastasis.

[3]  A. Howell,et al.  The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. , 1995, Endocrinology.

[4]  A. Reddi,et al.  Mechanisms of Tumor Metastasis to the Bone: Challenges and Opportunities , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[5]  S. Hilsenbeck,et al.  Somatic Mutation of p53 Leads to Estrogen Receptor α-Positive and -Negative Mouse Mammary Tumors with High Frequency of Metastasis , 2004, Cancer Research.

[6]  Paul J. Williams,et al.  Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. , 2002, Cancer research.

[7]  G. Bastert,et al.  Treatment of metastatic bone disease in breast cancer: bisphosphonates. , 2000, Clinical breast cancer.

[8]  E. Shtivelman,et al.  Colonization of human lung grafts in SCID‐hu mice by human colon carcinoma cells , 1996, International Journal of Cancer.

[9]  I. Fidler,et al.  Relative malignant potential of human breast carcinoma cell lines established from pleural effusions and a brain metastasis. , 1991, Invasion & metastasis.

[10]  T. Kudo,et al.  A new and efficient method to generate human IgG monoclonal antibodies reactive to cancer cells using SCID-hu mice. , 1995, Immunology letters.

[11]  Piyush B. Gupta,et al.  Disease models of breast cancer , 2004 .

[12]  R. Rubens.  The Nature of Metastatic Bone Disease , 1991 .

[13]  T. Yoneda,et al.  Over-expression of bone sialoprotein enhances bone metastasis of human breast cancer cells in a mouse model. , 2003, International journal of oncology.

[14]  Robert A. Weinberg,et al.  Creation of human tumour cells with defined genetic elements , 1999, Nature.

[15]  F. Miller,et al.  Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. , 1992, Cancer research.

[16]  G. Mundy.  Metastasis: Metastasis to bone: causes, consequences and therapeutic opportunities , 2002, Nature Reviews Cancer.

[17]  Keith R. Johnson,et al.  N-Cadherin Promotes Motility in Human Breast Cancer Cells Regardless of Their E-Cadherin Expression , 1999, The Journal of cell biology.

[18]  R. Cardiff,et al.  Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Cardiff,et al.  Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C. Cordon-Cardo,et al.  A multigenic program mediating breast cancer metastasis to bone. , 2003, Cancer cell.

[21]  R. Weinberg,et al.  Reconstruction of functionally normal and malignant human breast tissues in mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[22]  N. Kanomata,et al.  Establishment of a novel species- and tissue-specific metastasis model of human prostate cancer in humanized non-obese diabetic/severe combined immunodeficient mice engrafted with human adult lung and bone. , 2001, Cancer research.

[23]  A. Beck‐Sickinger.  G protein-coupled receptors, Tiina P. Iismaa, Trevor J. Biden, John Shine. Springer-Verlag (1995), 181, hard cover, ISBN: 1 57059 058 3 , 1996 .

[24]  W. Hahn,et al.  Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. , 2001, Genes & development.

[25]  D. Grignon,et al.  Severe combined immunodeficient-hu model of human prostate cancer metastasis to human bone. , 1999, Cancer research.

[26]  G D Roodman,et al.  Biology of osteoclast activation in cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  E. Shtivelman,et al.  Species-specific metastasis of human tumor cells in the severe combined immunodeficiency mouse engrafted with human tissue. , 1995, Proceedings of the National Academy of Sciences of the United States of America.