Cellular starvation kills treatment-resistant breast cancer

November 21, 2016

DURHAM, N.C. -- Cancer rewires the metabolism of tumor cells, converting them into lean, mean, replicating machines. But like Olympic athletes who rely on special diets to perform, tumor cells' amped-up metabolism can also make them dependent on specific nutrients for survival.

For years, scientists have been trying to identify and understand these cellular cravings in hopes of creating new cancer treatments that work by blocking off access to necessary nutrients and starving tumors to death.

In a new study, Duke University scientists report that cells from a vicious and treatment-resistant form of breast cancer, called triple negative breast cancer (TNBC), die off rapidly when deprived of a key nutrient called cystine. By examining the cause of cell death, they found that this "cystine addiction" is triggered by a mechanism that many kinds of tumor cells use to break away and migrate to new locations in the body.

"This process is well-known and shows up in metastatic cancer cells, and what we found is that it also makes the cells cystine-addicted," said Jen-Tsan Ashley Chi, associate professor of molecular genetics and microbiology at the Duke University School of Medicine and senior author on the study. "This is great news, because these are the cells that we really want to get rid of."

The results indicate that blocking cystine uptake may be an effective way of treating not only triple negative breast cancer, but other aggressive cancers that use this pathway during metastasis. The study appeared online Nov. 21 in Oncogene.

Patients diagnosed with triple negative breast cancer, which constitute about 10 to 20 percent of all breast cancer cases, have few treatment options outside of surgery and chemotherapy. That is because the most successful breast cancer therapies target two of three receptors commonly found in tumor cells -- estrogen receptor, progesterone receptor, or the Her2/neu receptor -- but triple negative breast cancer cells lack all three.

Some studies have hinted that these cells cannot survive without cystine, a molecule built from two copies of the amino acid cysteine linked together.

Earlier this year, Chi's group published a study showing that cells from an aggressive form of kidney cancer are addicted to cystine. To find out if this was also true for triple negative breast cancer, Xiaohu Tang, a previous postdoctoral fellow in Chi lab, submitted both triple-negative and estrogen-positive breast cancer cells to a nutrient deprivation test: growing batches of each cell type in a series of different growth media, each missing just one out of 15 key amino acids.

Most of the cells showed little reaction to these small changes in diet, Chi said. But there was one notable exception.

"The triple negative breast cancer cells were very sensitive to cystine," Chi said. "So if you removed cystine, they just rapidly died, while the other breast cancer cells didn't care."

They subjected the cells to a battery of genetic analyses to pinpoint the cause. They found that the cystine addiction is linked to a process called the epithelial to mesenchymal transition (EMT), a bit of genetic programming that allows stationary epithelial cells, usually stuck in place by tough, zipper-like molecules, to transform themselves into roving mesenchymal cells.

The triple negative breast cancer cells, along with a number of other types of cancer cells, tap into this process to break away from their neighbors and metastasize to spread throughout the body, Chi says. But it appears that this process also triggers a cellular signaling pathway that leads to rapid death as soon as cystine is not available.

"We found that this transition between epithelial and mesenchymal basically opens up a signaling difference that makes the cells very vulnerable to cystine deprivation, leading to death," Chi said. "It is almost like EMT is opens up a whole highway system (for cystine-mediated death), and therapeutically this could be very useful because there are actually compounds to block this."

Chi says the team is now in the process of testing out these cystine-blocking molecules on tumors and searching for biomarkers that will help identify when cancers are likely to respond positively to this treatment.

"Tumor cells use this EMT programming to move faster, to move around the body," Chi said. "We want to take advantage of this same pathway to cure you."
This research was supported by funding from the National Institutes of Health (CA125618 and CA106520) and the Department of Defense (W81XWH-12-1-0148, W81XWH-14-1-0309 and W81XWH-15-1-0486).

CITATION: "Cystine addiction of triple negative breast cancer associated with EMT augmented death signaling," Xiaohu Tang, Chien-Kuang Ding, Jianli Wu, et al. Oncogene, online Nov. 21, 2016. DOI: # 10.1038/onc.2016.394

Duke University

Related Breast Cancer Articles from Brightsurf:

Oncotarget: IGF2 expression in breast cancer tumors and in breast cancer cells
The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.

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.

Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.

Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.

Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.

Read More: Breast Cancer News and Breast Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.