Restoring tamoxifen sensitivity in resistant breast cancer cells

December 20, 2006

The widely used breast cancer drug tamoxifen (Nolvadex®), which can become less effective over time, might retain its full strength indefinitely if used along with a second drug, according to new research in mice conducted by investigators from the National Cancer Institute (NCI), part of the National Institutes of Health, and their partners. The results appear in the December 11, 2006, issue of Cancer Cell*.

Tamoxifen has been used successfully since the 1970s to treat certain types of breast cancer and to prevent them from recurring after surgery. Clinicians observed that tamoxifen treatment initially reduced the rate of recurrence by nearly 50 percent. Over time, however, patients develop resistance to the drug and tamoxifen loses its effectiveness as a cancer treatment.

"Tamoxifen has been extremely important in the management of breast cancer," said NCI Director John E. Niederhuber, M.D. "Being able to overcome resistance would be an important advance."

In the study, the research team, led by William Farrar, Ph.D., of NCI's Center for Cancer Research at Frederick, Md., found that the effectiveness of tamoxifen in cell cultures and in mice can be fully restored by the use of a compound called disulfide benzamide, or DIBA. The investigators confirmed their study hypothesis about DIBA's effect on tamoxifen resistance by using the compound in mice that were engineered to have tamoxifen-resistant tumors and saw that tumor growth was reduced by nearly 50 percent when DIBA was administered.

"Exposure to DIBA causes certain physical changes to occur between the estrogen receptor and the biological machinery that stimulates cell division. By coincidence, these changes also restore the estrogen receptor to a form that makes it vulnerable once again to tamoxifen," said Li Hua Wang, Ph.D., lead author of the study.

Some, but not all, breast cancer cells have specific receptors that bind estrogen molecules circulating in the bloodstream. When estrogen binds to the estrogen receptor, it triggers a series of events that promote cell division. If the cell is a breast cancer cell, this interaction leads to tumor growth. In women with estrogen receptor-positive cancers, cancer cell growth is strongly influenced by estrogen.

Tamoxifen works by binding to estrogen receptors in place of estrogen and blocking the signals that lead to cell division. Initially, tumor growth slows or stops altogether. With continued tamoxifen treatment, however, the estrogen receptor and the estrogen-dependent signaling pathways in the cell can become altered, rendering tamoxifen ineffective as an inhibitor. In some cases, tamoxifen begins to act like estrogen and can stimulate tumor growth.

DIBA and related compounds are being studied because of their ability to disrupt cellular activity at the genetic level. These so-called electrophilic compounds were first investigated for possible use against AIDS because they can block the human immunodeficiency virus (HIV) from replicating. The HIV studies are ongoing.

"This basic study generated exciting results in our mouse model and suggests a promising approach that might be tried in human patients," said Farrar. His laboratory is now exploring ways to produce DIBA in a form that is water soluble so it could be administered as a pill, the same as tamoxifen. If successful, this could set the stage for preclinical studies.
-end-
Collaborators on the research include Georgetown University, Washington, D.C., Baylor College of Medicine and The Methodist Hospital, Houston, Texas, and the National Institute of Allergy and Infectious Diseases, Bethesda, Md.

* Wang LH, Yang XY, Zhang X, An P, Kim H, Huang J, Clarke R, Osborne CK, Inman JK, Appella E, and Farrar WL. Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer. Cancer Cell, December 11, 2006; Vol. 10, Issue 6.

For more information on Dr. Farrar's research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5618.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Leidos Biomedical Research, Inc.

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.