Featured Research

from universities, journals, and other organizations

Gene that controls aggressiveness in breast cancer cells identified

Date:
July 3, 2013
Source:
Whitehead Institute for Biomedical Research
Summary:
Researchers have determined that in basal breast cancer cells a transcription factor known as ZEB1 is held in a poised state, ready to increase the cells’ aggressiveness and enable them to transform into cancer stem cells capable of seeding new tumors throughout the body. Intriguingly, luminal breast cancer cells, which are associated with a much better clinical prognosis, carry this gene in a state in which it seems to be permanently shut down.

Cells from basal cancers are able to switch relatively easily into cancer stem cell (CSC) state, unlike luminal breast cancer cells, which tend to remain in the non-CSC state. The gene ZEB1 is critical for this conversion. The difference in ZEB1’s effects is due to the way the gene is marked in the two types of cancers. In luminal breast cancer cells, the ZEB1 gene is occupied with modifications that shut it down. But in basal breast cancer cells, ZEB1’s state is more tenuous, with repressing and activating markers coexisting on the gene. When these cells are exposed to certain signals, including those from TGFß, the repressive marks are removed and ZEB1 is expressed, thereby converting the basal non-CSCs into CSCs.
Credit: Image courtesy of Whitehead Institute for Biomedical Research

In a discovery that sheds new light on the aggressiveness of certain breast cancers, Whitehead Institute researchers have identified a transcription factor, known as ZEB1, that is capable of converting non-aggressive basal-type cancer cells into highly malignant, tumor-forming cancer stem cells (CSCs). Intriguingly, luminal breast cancer cells, which are associated with a much better clinical prognosis, carry this gene in a state in which it seems to be permanently shut down.

Related Articles


The researchers, whose findings are published this week in the journal Cell, report that the ZEB1 gene is held in a poised state in basal non-CSCs, such that it can readily respond to environmental cues that consequently drive those non-CSCs into the dangerous CSC state. Basal-type breast carcinoma is a highly aggressive form of breast cancer. According to a 2011 epidemiological study, the 5-year survival rate for patients with basal breast cancer is 76%, compared with a roughly 90% 5-year survival rate among patients with other forms of breast cancer.

"We may have found a root source, maybe the root source, of what ultimately determines the destiny of breast cancer cells -- their future benign or aggressive clinical behavior," says Whitehead Founding Member Robert Weinberg, who is also a professor of biology at MIT and Director of the MIT/Ludwig Center for Molecular Oncology.

Transcription factors are genes that control the expression of other genes, and therefore have a significant impact on cell activities. In the case of ZEB1, it has an important role in the so-called epithelial-to-mesenchymal transition (EMT), during which epithelial cells acquire the traits of mesenchymal cells. Unlike the tightly-packed epithelial cells that stick to one another, mesenchymal cells are loose and free to move around a tissue. Previous work in the Weinberg lab showed that adult cancer cells passing through an EMT are able to self-renew and to seed new tumors with high efficiency, hallmark traits of CSCs.

Other earlier work led by Christine Chaffer, a postdoctoral researcher in the Weinberg lab, demonstrated that cancer cells are able to spontaneously become CSCs. Now Chaffer and Nemanja Marjanovic have pinpointed ZEB1, a key player in the EMT, as a gene critical for this conversion in breast cancer cells.

Breast cancers are categorized into at least five different subgroups based on their molecular profiles. More broadly these groups can be subdivided into the less aggressive 'luminal' subgroup or more aggressive 'basal' subgroup. The aggressive basal-type breast cancers often metastasize, seeding new tumors in distant parts of the body. Patients with basal breast cancer generally have a poorer prognosis than those with the less aggressive luminal-type breast cancer.

Chaffer and Marjanovic, a former research assistant in the Weinberg lab, studied non-CSCs from luminal- and basal-type cancers and determined that cells from basal cancers are able to switch relatively easily into CSC state, unlike luminal breast cancer cells, which tend to remain in the non-CSC state.

The scientists determined that the difference in ZEB1's effects is due to the way the gene is marked in the two types of cancers. In luminal breast cancer cells, the ZEB1 gene is occupied with modifications that shut it down. But in basal breast cancer cells, ZEB1's state is more tenuous, with repressing and activating markers coexisting on the gene. When these cells are exposed to certain signals, including those from TGFß, the repressive marks are removed and ZEB1 is expressed, thereby converting the basal non-CSCs into CSCs.

So what does this new insight mean for treating basal breast cancer?

"Well, we know that these basal breast cancer cells are very plastic and we need to incorporate that kind of thinking into treatment regimes," says Chaffer. "As well as targeting cancer stem cells, we also need to think about how we can prevent the non-cancer stem cells from continually replenishing the pool of cancer stem cells. For example, adjuvant therapies that inhibit this type of cell plasticity may be a very effective way to keep metastasis at bay."

Marjnaovic agrees but cautions that the model may not be applicable for every cancer.

"This is an example of how adaptable cancer cells can be,," says Marjanovic, who is currently a research assistant at the Broad Institute. "We have yet to determine if ZEB1 plays a similar role in all cancer types, but the idea that cancer cells reside in a poised state that enables them to adapt to changing environments may be a mechanism used by many cancers to increase their aggressiveness."

This work is supported Vertex Scholars Program, the National Science Foundation (NSF), Jerome and Florence Brill Fellowship, Croucher and Ludwig Research Fellowship, the National Institutes of Health (NIH) (1 F32 GM099153-01A1, HD 045022 and R37CA084198).


Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. The original article was written by Nicole Giese Rura. Note: Materials may be edited for content and length.


Journal Reference:

  1. Christine L. Chaffer, Nemanja D. Marjanovic, Tony Lee, George Bell, Celina G. Kleer, Ferenc Reinhardt, Ana C. D’Alessio, Richard A. Young, Robert A. Weinberg. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell, 2013 DOI: 10.1016/j.cell.2013.06.005

Cite This Page:

Whitehead Institute for Biomedical Research. "Gene that controls aggressiveness in breast cancer cells identified." ScienceDaily. ScienceDaily, 3 July 2013. <www.sciencedaily.com/releases/2013/07/130703120557.htm>.
Whitehead Institute for Biomedical Research. (2013, July 3). Gene that controls aggressiveness in breast cancer cells identified. ScienceDaily. Retrieved November 24, 2014 from www.sciencedaily.com/releases/2013/07/130703120557.htm
Whitehead Institute for Biomedical Research. "Gene that controls aggressiveness in breast cancer cells identified." ScienceDaily. www.sciencedaily.com/releases/2013/07/130703120557.htm (accessed November 24, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Monday, November 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola-Hit Sierra Leone's Late Cocoa Leaves Bitter Taste

Ebola-Hit Sierra Leone's Late Cocoa Leaves Bitter Taste

AFP (Nov. 23, 2014) — The arable district of Kenema in Sierra Leone -- at the centre of the Ebola outbreak in May -- has been under quarantine for three months as the cocoa harvest comes in. Duration: 01:32 Video provided by AFP
Powered by NewsLook.com
Don't Fall For Flu Shot Myths

Don't Fall For Flu Shot Myths

Newsy (Nov. 23, 2014) — Misconceptions abound when it comes to your annual flu shot. Medical experts say most people older than 6 months should get the shot. Video provided by Newsy
Powered by NewsLook.com
WFP: Ebola Risks Heightened Among Women Throughout Africa

WFP: Ebola Risks Heightened Among Women Throughout Africa

AFP (Nov. 21, 2014) — Having children has always been a frightening prospect in Sierra Leone, the world's most dangerous place to give birth, but Ebola has presented an alarming new threat for expectant mothers. Duration: 00:37 Video provided by AFP
Powered by NewsLook.com
Could Your Genes Be The Reason You're Single?

Could Your Genes Be The Reason You're Single?

Newsy (Nov. 21, 2014) — Researchers in Beijing discovered a gene called 5-HTA1, and carriers are reportedly 20 percent more likely to be single. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins