Toughest breast cancer may have met its match

December 08, 2014

Triple-negative breast cancer is as bad as it sounds. The cells that form these tumors lack three proteins that would make the cancer respond to powerful, customized treatments. Instead, doctors are left with treating these patients with traditional chemotherapy drugs that only show long-term effectiveness in 20 percent of women with triple-negative breast cancer. Now, researchers at The Johns Hopkins University have discovered a way that breast cancer cells are able to resist the effects of chemotherapy -- and they have found a way to reverse that process.

A report of their findings was published online in the journal Proceedings of the National Academy of Sciences on Dec. 1.

Triple-negative breast cancers account for about 20 percent of all breast cancers in the United States, and 30 percent of all breast cancers in African-American women. In addition to being resistant to chemotherapy, they are known to include a high number of breast cancer stem cells, which are responsible for relapses and for producing the metastatic tumors that lead to the death of patients with cancer. Previous research revealed that triple-negative breast cancer cells show a marked increase in the activity of many genes known to be controlled by the protein hypoxia-inducible factor (HIF). Given these past results, a research team directed by Gregg Semenza, M.D., Ph.D., decided to test whether HIF inhibitors could improve the effectiveness of chemotherapy.

"Our study showed that chemotherapy turns on HIF and that HIF enhances the survival of breast cancer stem cells, which are the cancer cells that must be killed to prevent relapse and metastasis," says Semenza, the C. Michael Armstrong Professor of Medicine at Johns Hopkins and a Johns Hopkins Kimmel Cancer Center expert. "The good news is that we have drugs that block HIF from acting."

Semenza's study began by treating lab-grown triple-negative breast cancer cells with the chemotherapy drug paclitaxel and looking for changes in HIF levels. After four days of treatment, HIF protein and activity levels had increased, as had the percentage of breast cancer stem cells among the surviving cells. When Semenza's team, led by postdoctoral fellow Debangshu Samanta, Ph.D., genetically altered the cancer cells to have less HIF, the cancer stem cells were no longer protected from death by chemotherapy, demonstrating that HIF was required for the cancer stem cells to resist the toxic effects of paclitaxel, Semenza says.

At the molecular level, the team found that one of the ways HIF enhances the survival of the stem cells is by increasing the levels of a protein, multidrug resistance protein 1 (MDR1), which acts like a pump to expel chemotherapy from cancer cells. However, when triple-negative breast cancer cells were given paclitaxel plus the HIF inhibitor digoxin, MDR1 levels went down rather than up.

In mice that were implanted with triple-negative breast cancer cells, treatment with digoxin and paclitaxel decreased tumor size by 30 percent more than treatment with paclitaxel alone. The combination therapy also decreased the number of breast cancer stem cells and the levels of MDR1. Treatment with digoxin plus a different chemotherapy drug, gemcitabine, brought tumor volumes to zero within three weeks and prevented the immediate relapse at the end of treatment that was seen in mice treated with gemcitabine alone.

Analysis of patient databases showed that among women with triple-negative breast cancer who are treated with chemotherapy, those with higher-than-average levels of HIF activity in their tumor were much more likely to die of breast cancer than those with lower-than-average HIF levels. Samanta notes that the HIF inhibitor digoxin is already approved by the Food and Drug Administration for treating heart failure. Several other drugs that inhibit HIF have also been identified and are currently being tested in patients with cancer. If the team's work is verified in clinical trials, the researchers think that potentially unresponsive patients could be identified before treatment and given a more effective combination therapy.
-end-
Fast Facts Other authors of the report include Daniele Gilkes, Pallavi Chaturvedi and Lisha Xiang of the Johns Hopkins University School of Medicine.

This work was supported by grants from the Department of Defense (W81XWH-12-1-0464), the Maryland Department of Health and Mental Hygiene (FH-B33-CRF), the Cindy Rosencrans Fund for Triple Negative Breast Cancer, the WTFC Organization and the National Cancer Institute (K99-CA181352).

On the Web

View the article at PNAS. http://dx.doi.org/10.1073/pnas.1421438111

Learn more about Semenza: http://www.hopkinsmedicine.org/profiles/results/directory/profile/800056/gregg-semenza

Related stories: http://www.hopkinsmedicine.org/institute_cell_engineering/experts/meet_scientists/gregg_semenza.html

Johns Hopkins Medicine

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.