Lab mice have grown tissue more usually confined to a bra - lumps of human breast. The growths should help researchers work out how cancer develops.
Researchers commonly use genetically engineered mice to study cancer, but the animal disease differs slightly from the human one. So researchers have sought to transplant human breast tissue into mice to make a better model.
Now Robert Weinberg of the Whitehead Institute for Biomedical Research in Boston and his team have succeeded. They report their method in the Proceedings of the National Academy of Sciences1.
The key, Weinberg says, is to transplant two types of human breast cells into the mice, one of which has been blasted with radiation.
The cells grow into human-like breast tissues, complete with milk ducts. Unlike human breasts, however, the mice's growths sit flush to the chest. Humans are unusual in this respect, says Daniel Medina who studies breast cancer at Baylor College of Medicine at Houston, Texas: "In few other species are breasts pendulous."
Hocus-pocus
In the past, some researchers transplanted only one type of breast cell, called epithelial cells, into mice. These cells line the milk ducts, and are where breast cancers start. But such attempts were "doomed to failure", says Weinberg, because they lacked a second element of human breast tissue - support cells called fibroblasts.
So Weinberg's team took fibroblast tissue from women who had undergone breast reduction surgery. They blasted half the fibroblasts with X-rays, injected both healthy and irradiated cells into mouse mammary glands, and grafted human epithelial breast cells alongside.
Weinberg thinks that irradiating the fibroblasts helps the epithelial cells survive. He is not sure how it works, but it may provoke an inflammatory response that helps to protect the cells. "It's hocus-pocus," he says.
The human-breasted mice also develop cancer in much the same way as humans. Scientists think breast cancer starts when one epithelial cell gets a mutation in its DNA and starts dividing wildly into a tumour.
When the team modified the human fibroblasts so that they made a protein often over-produced in human breast tumours, the mice developed cancer in their epithelia.
This suggests that the transplanted epithelial cells were harbouring mutations that turned cancerous in response to signals from neighbouring cells. Researchers hope the new system will help them tease out these signals and, perhaps, find ways to stall them. "It's a very big advance," says Medina.
References
Kuperwasser, C. et al. Proc. Natl. Acad. Sci., published online, doi:10.1073/pnas.0401064101 (2004). [Abstract below]
Charlotte Kuperwasser *, Tony Chavarria *, Min Wu , Greg Magrane , Joe W. Gray , Loucinda Carey *, Andrea Richardson ¶, and Robert A. Weinberg * *Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142; GenPath Pharmaceuticals, Incorporated, 300 Technology Square, 7th Floor, Cambridge, MA 02139; University of California San Francisco Comprehensive Cancer Center, 2340 Sutter Street, Room N415, San Francisco, CA 94143-0808; and ¶Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115
Contributed by Robert A. Weinberg, February 13, 2004
The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.
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To whom correspondence should be sent at the present address: Department of Physiology, Tufts University School of Medicine, 136 Harrison Avenue 701, Boston, MA 02111.
Charlotte Kuperwasser , E-mail: charlotte.kuperwasser@tufts.edu
www.pnas.org/cgi/doi/10.1073/pnas.0401064101
source: http://www.pnas.org/cgi/content/abstract/0401064101v1 2apr04
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