Gene deletion drives more than a quarter of breast cancers

August 15, 2012 By Krishna Ramanujan, Cornell University
The image shows two tumors in mice from transplanted tumor-prone mammary gland stem cells. The tumor on the left was manipulated to have a reduced amount of NF1 protein (expressed by the NF1 gene), while the one on the right has normal NF1 levels. This preliminary experiment supports a critical role for NF1 in suppressing breast cancer. Image: Schimenti Lab

A new study shows that the lack of a certain gene occurs in almost 28 percent of human breast cancers, playing a role in some 60,000 breast cancer cases in the United States and 383,000 worldwide this year.

Recent studies have observed loss of the gene NF1 in glioblastoma (an aggressive ), lung and , but the significance has been overlooked because it was thought that two copies of the gene (one from each parent) needed to be missing to cause cancer. The study, published online July 30 in the journal Genetics, reports that in most human cases where NF1 is a factor, only one copy is missing.

The finding has important . It suggests that several existing drugs may be effective in treating breast cancers with missing NF1; it also suggests that the commonly used tamoxifen could make the disease worse in these specific cancers.

The NF1 gene negatively regulates one of the most important oncogenes -- genes that when mutated or expressed at high levels contribute to turning a normal cell into a cancerous one. This , called RAS, is involved in signaling inside the cell to control growth. When NF1 is missing or depleted, RAS becomes hyperactivated and can lead to .

In the study, Cornell researchers used a with elevated that lead to breast cancer in 80 percent of the mice.

"These mice almost always get , and when we looked at their genomes, nearly all of them were missing this NF1 gene," said John Schimenti, professor of genetics and the paper's senior author. "There are many big that identify the most commonly mutated genes, but they don't prove experimentally that those genes are the drivers of cancer."

In humans, there are many causes of breast cancer, and each patient's cancer has a slightly different set of natural gene variants as well as new mutations in their tumors, so identifying individual genes that drive cancer can be problematic. But the model mice are inbred and get exactly the same tumor every time. "So we've eliminated all the noise," allowing the researchers to identify NF1 as a driver of these tumors, said Schimenti.

In the mouse model, RAS is hyperactivated. Since RAS is one of the most important oncogenes, many drugs have been already developed to interrupt the RAS pathway to treat cancer.

"If NF1 is missing and it is causing cancer by activating RAS, then these drugs may help," said Schimenti. "Therefore, there doesn't need to be any more drug development to test this possibility right now," he added.

The study also suggests that tamoxifen, one of the most common breast cancer treatments, may exacerbate the disease when the missing NF1 is the driver. Another study reported that NF1 protein depletion makes cancer cells resistant to tamoxifen, and tamoxifen-treated patients whose tumors have low NF1 levels had poorer clinical outcomes.

Schimenti and his colleagues plan to test whether they can reverse growth of tumors in mice missing the NF1 gene by inserting a replacement gene. They are also testing how effective RAS inhibitor drugs are at curbing cancer in mice. The paper shows that RAS inhibitors curb growth of these tumor cells in culture.

Marsha Wallace, a graduate student working in Schimenti's lab, is the paper's lead author. Researchers from the University of North Carolina and Sloan Kettering Cancer Center co-authored the study.

The study was funded by the National Institutes of Health, the Empire State Stem Cell Fund, the National Cancer Institute and the Breast Cancer Research Foundation.

Explore further: New study identifies novel role for PEA-15 protein in cancer growth

Related Stories

New study identifies novel role for PEA-15 protein in cancer growth

November 21, 2011
A new study from the University of Hawaii Cancer Center reveals that PEA-15, a protein previously shown to slow ovarian tumor growth and metastasis, can alternatively enhance tumor formation in kidney cells carrying a mutation ...

Pediatric tumors traced to stem cells in developing brain

July 9, 2012
Stem cells that come from a specific part of the developing brain help fuel the growth of brain tumors caused by an inherited condition, researchers at Washington University School of Medicine in St. Louis report.

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

JGHunter
not rated yet Aug 15, 2012
Would it be too simplistic to have people tested for presence of NF1, so if they have it, they can be prepared for it?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.