Triple Step to Cancer


CAMBRIDGE, Mass. — Doctors delivered a one-two-three punch to healthy adult breast tissue, and, for the first time, made it cancerous, bringing scientists closer to understanding the complex process of how normal breast tissue becomes diseased.

While other experiments have been able to turn normal cells into tumor cells, also using genes, those experiments used easy-to-grow cells such as embryonic kidney cells and cells taken from the foreskin.

The latest research, however, used cancer-linked genes to turn human mammal epithelial cells (HMECs) into cancerous cells. Epithelial cells make up the “lining” for vessels and body cavities, including the breast. Most naturally occurring cancers start from epithelial cells.

Using three genes called SV40 large-T, telomerase hTERT and oncogenic H-rasV12, lead researcher Brian Elenbaas and his colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Mass., were able to feed in them in, one gene at a time to make the normal breast tissue cells into breast cancer cells. These three genes have to do with cell growth and survival.

Elenbaas, a postdoctoral fellow, used normal breast cells taken from tissue removed during breast reduction surgeries, and introduced the three genes, one after the other. You need all three genes for the cells to become cancerous.

“The first gene?enables the cell to get around two periods of growth arrest. The second gene has to come in to enable the cells to become immortal and bypass the third growth-arrest phase,” says Elenbaas. “Once the cells are immortalized, they’re still not tumerogenic. They require one additional gene, and that’s the ras oncogene.”

To prove that it made the cells cancerous, the team injected the transformed cells into mice, where tumors with some of the characteristics of breast cancers formed. The researchers also found that the microenvironment — the area surrounding the tumor — influenced how fast the tumors formed.

When breast cancer cells are able to signal and communicate with the cells around them, they grow more quickly. “Such signaling mechanisms would be potential therapeutic targets in the future.”

Furthermore, these cancerous cells appear to be more like the primary tumors that appear in the breast. This is helpful, says, Elenbaas, because many of the breast cancer cell lines that are routinely used in laboratory tests are actually taken from metastasized breast cancer, usually cells that have spread to the lungs. “In those cell lines, there are many genetic mutations,” says Elenbaas, or they may have an abnormal number of chromosomes.

The new cancer cells produced in this study are more like primary tumors. However, they don’t spread, and the team is trying to find the gene that will prompt the cancer to take that step.

“We’ve created a new model for breast cancer, in which we can start to define with precision the genetic steps that are required in this process of converting normal cells into tumor cells,” says Elenbaas.

According to Colette Freeman, the chief of the Cancer Cell Biology Branch at the National Cancer Institute in Bethesda, Md., “we suspect that cancer is caused by a number of what we call genetic ‘hits’ — that is, mutations in specific genes. [The study] confirms the fact that it probably takes multiple genetic hits?at least three, in order for a normal cell to become cancer.”

About 10 percent of breast cancers are linked to genetic mutations, and studies have linked the disease to changes of the BRCA1 and BRCA2 genes. About 50 percent to 60 percent of women who have inherited one of these mutated genes from either parent will develop breast cancer by the age of 70.

Breast cancers don’t typically involve the ras oncogene, says Elenbaas. Instead, a gene called HER-2 often plays a role, and the team is now trying to replace ras with the HER-2 gene. “It would more accurately mimic a genetic change that occurs in a real primary breast tumor.”

By adding to the basic understanding of breast cancer, says Elenbaas, these findings may not produce new treatment in the immediate future, but eventually, this and other cell lines could be used to test new drugs.