September 18, 2012

Scientists in Prof. John Schimenti’s Lab Find Gene Linked to Breast Cancer

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There are many unknown drivers behind cancer, but the lab of Prof. John Schimenti has discovered that about 28 percent of breast cancer cases are linked to a single gene.

The drivers behind cancer are numerous and, in many cases, unknown. Recently, the lab of Prof. John Schimenti, molecular biology and genetics, discovered that about 28 percent of breast cancer cases are linked to a single gene.

Schimenti’s lab studied mice that had a single mutation in a DNA replication gene called MCM4. This mutated gene causes mammary tumors, which are the mouse equivalent of breast cancer, in nearly every case.

“With the MCM4 mutation, specific regions of DNA are getting extra copies or being lost.” Marsha Wallace, grad, said.

After studying the tumors, they found that all of the tumors were losing a gene called NF1, a known tumor suppressor. NF1 specifically controls an oncogene, or cancer producing gene, called RAS.

Oncogenes are normally present in cells, but when active in the absence of a tumor suppressor, they can cause the cell to turn cancerous. RAS is an important oncogene that causes uncontrollable growth in cells, but RAS is not commonly associated with breast cancer.

In order to associate RAS with breast cancer, Schimenti’s lab took advantage of The Cancer Genome Atlas (TCGA) Project, a database of sequenced and analyzed genomes for multiple forms of cancer from hundreds of patients. The database revealed that mutations in the NF1 gene were also found in human breast cancer patients.

“Because the mice were almost always losing NF1 in the mammary tumors, and humans are commonly missing NF1, we think that NF1 loss is important in a substantial percentage of human breast cancers,” Schimenti said.

The lab’s research linking mutated NF1 genes to breast cancer may seriously affect treatment for the disease. In an unrelated study earlier this year, cells with mutated or missing NF1 genes were shown to have an increased resistance to the most commonly used drug in breast cancer, tamoxifen. Breast cancer patients who have a mutation in NF1 may want to look for drugs that inhibit RAS instead.

“This could impact about 283,000 breast cancer patients every year,” Wallace said.

“Cancer is a multi-step process, multiple things have to go wrong inside a cell and we think this is one of them,” Schimenti said.

A possible next step for the project is to reintroduce NF1 into the cancerous cells of mice to see if it can inhibit uncontrollable cell growth and reduce tumors.

Original Author: Sarah Cohen