Nav: Home

Protein identified by Mass. General team may protect tumor-initiating breast cancer cells

January 16, 2017

Massachusetts General Hospital investigators have identified a protein that may play an essential role in maintaining a population of tumor-initiating cells (TICs) -- treatment-resistant cells responsible for cancer recurrence and metastasis -- in breast cancer, as well as a compound that appears to reduce the molecule's ability to protect TICs from the effects of chemotherapy. Results of the team's study are being published online in PNAS.

"The protein we have identified -- G3BP2 -- affects the survival and proliferative potential of breast cancer cells by regulating the ratio of TICs to non-TICs within a tumor," says Igor Garkavtsev, MD, PhD, of the Steele Laboratories of Tumor Biology in the MGH Radiation Oncology Department, who led the study. "We also found that G3BP2 regulates breast tumor initiation in a way that leads to the increased expression of Oct-4 and Nanog, transcription factors contributing to the pluripotency of embryonic stem cells."

Breast cancers are made up of many different cell types, and it is believed that TICs, while making up a very small proportion of tumors, are capable of generating the full range of cancer cells. TICs may be present in most types of cancer; and since they seem to resist common therapies, finding ways to directly target TICs -- which requires better understanding of the mechanisms by which they are generated and maintained -- could significantly improve cancer treatment.

The MGH team began by treated a metastatic breast cancer cell line, which would be expected to contain a significant proportion of TICs, with combinations of the chemotherapy drug paclitaxel and compounds from a library of more than 60,000 diverse small molecules. From those compounds that increased the ability of paclitaxel to reduce the survival of cancer cells, they identified the one with the most pronounced effect, which they called compound C108.

Testing that compound in a different line of TIC-enriched breast cancer cells not only confirmed its ability to increase the toxic effect of paclitaxel but also showed that compound C108 alone could reduce the proportion of TICs in a population of cells. After implantation into mice, breast cancer cells that had been treated with compound C108 were observed to have an approximately 10-fold reduction in the proportion of TICs, compared with implanted cells that had been treated with an inert compound.

Further experiments showed that compound C108 exerts its effect through G3BP2, a protein found in cellular structures called stress granules, which are formed to protect RNA molecules from stresses such as oxygen deprivation or toxins - including chemotherapy drugs. Screening genetic samples from more than 4,000 breast cancer patients revealed that those with higher levels of G3BP2 expression had significantly worse outcomes, with increased tumor recurrence and metastasis.

More detailed analysis revealed that G3BP2 regulates breast tumor initiation by controlling the levels of TICs within tumors. The protein exert its effects by stabilizing the mRNA of SART3 -- a protein that plays a role in the pluripotency, the ability to give rise to any type of cell, of embryonic stem cells -- leading to increased expression of pluripotency factors Oct-4 and Nanog.

"The possibility that some breast cancer cells with vast proliferative potential may be intrinsically resistant to standard therapies may partially explain why tumors relapse after treatment," says Garkavtsev, who is an assistant professor of Radiation Oncology at Harvard Medical School. "Our identification of compound C108 and the discovery of G3BP2 as a potential regulator of TICs open opportunities for further exploration of the mechanisms of breast cancer initiation and the development of novel therapies. Combining derivatives of compound C108 with standard treatments could benefit patients with relapsed, drug-resistant or metastatic breast cancer and improve their survival."
-end-
The co-lead authors of the PNAS paper are Nisha Gupta and Mark Badeaux of the Steele Labs and Yiqian Liu of Jiangsu Province Hospital in Nanjing, China. Additional co-authors are Kamila Naxerova, PhD, Lance L. Munn, PhD, and Rakesh K. Jain, PhD, of the Steele Labs; and Dennis Sgroi, MD, of the MGH Department of Pathlogy. Support for the study includes National Institutes of Health grant R21CA169616, a grant from the Federal Share Proton Beam Program, SPARC and a Department of Defense Breast Cancer Research Innovator Award.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Breast Cancer Articles:

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.
Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.
More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.
Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.
Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.
More Breast Cancer News and Breast Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...