Three genetic steps convert normal mammary cells into breast cancer cells

December 31, 2000

Cells originating from normal human breast tissue have been converted into breast cancer cells by a defined protocol of genetic changes. In the January 1 issue of Genes & Development, Dr. Robert Weinberg and colleagues from MIT report that the sequential introduction of three cancer-associated genes into human mammary epithelial cells (HMECs) renders these cells tumorigenic. This study is the first report of the successful transformation of epithelial cells originating from a differentiated adult tissue such as the mammary gland. Cancers arising from epithelial cells account for the majority of naturally occurring malignancies, and breast cancer in particular is one of the leading causes of cancer related deaths in the United States. Thus far, the genetic complexity of breast cancer cells has made it difficult to identify the specific genetic alterations that are required for the switch from a normal cell to a tumor cell. Identification of the minimal genetic requirements of tumorigenesis will help to understand the mechanisms underlying the uncontrolled and destructive growth behavior of cancer.

The genes chosen for use in this experiment - SV40 large-T, telomerase hTERT and oncogenic H-rasV12 - interfere with essential regulatory pathways governing cellular growth and survival. The sequential introduction of these three genes into HMECs results in cells that display the typical properties of malignant cells in culture, and form aggressive tumors when transplanted into mice. In addition, the researchers detected in the artificially transformed cells amplifications of the c-myc oncogene, another gene that is frequently mutated in breast cancer. Therefore, this in vitro transformation protocol did not only produce malignant mammary cells, but did also initiate a process of additional events which recapitulate further genetic alterations typically found in the spontaneous development of breast cancer in patients.

An important observation made by Dr. Weinberg and colleagues is that the co-injection of components naturally found in the environment surrounding epithelial cells can substantially facilitate the formation of tumors upon transplantation in mice. This finding supports the hypothesis that cancer is not only the autonomous and uncontrolled growth of a transformed cell, but that it also relies on a specific cross-talk between the tumor and its microenvironment. Finally, this interaction is believed to play a central role in metastasis, the most threatening stage in cancer progression. Both genetic alterations within the cancer cell as well as specific reactions of the surrounding normal cells, are therefore the subject of intense research. Given the effectiveness of this three-step-transformation protocol in generating breast cancer cells in vivo, scientists expect this system to be useful in elucidating the complex process of tumor development, and ultimately to provide a tool for studying novel therapies.

Cold Spring Harbor Laboratory

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