Hutch News Stories

New and better cancer-prevention drugs?

Collins brings 25 years of research to bear on seeking a better understanding of tamoxifen's mechanisms
Dr. Steve Collins
Dr. Steve Collins examines tissue-culture flasks containing the breast epithelial cells he uses to to study the estrogen receptor and the retinoic-acid receptor, two targets of chemopreventive drugs. Photo by Clay Eals

A pill to prevent cancer? It's not just future fantasy. Thousands of women take a daily dose of tamoxifen, which delivers a targeted strike to breast tissue and, for some, cuts the risk of breast cancer by nearly half.

Though the effect of tamoxifen on cancer prevention is encouraging, some scientists - including by Dr. Steve Collins, a Hutch investigator in the Human Biology Division - wonder whether the statistics can be improved with a better understanding of the drug's mechanism of action.

Collins, who has 25 years of experience in leukemia research, noticed an opportunity to do just that while studying a connection between a pathway he studies in leukemia cells and a protein with a role in breast cancer.

His new research in this area is funded by a $200,000 pilot grant from the Susan G. Komen Breast Cancer Foundation awarded last spring.

Collins' studies focus on a pair of cellular receptors with dueling roles in cell multiplication.

The estrogen receptor, a key player in the development of many breast tumors, triggers a cascade of events leading to breast-cell multiplication when it's confronted with the female hormone estrogen. Tamoxifen - called an anti-estrogen - docks on the receptor in the same place as estrogen, plugging up the receptor and rendering it inactive.

In contrast, the retinoic-acid receptor, which is found in a variety of cell types, halts cell proliferation when it responds to its allied molecule, the vitaminA derivative retinoic acid.

Earlier study of retinoic acid

In earlier work, Collins exploited the function of retinoic acid, research that led to an effective therapy for a rare form of leukemia. Retinoic acid also is being tested in clinical trials to see if it might inhibit breast cancer.

Collins suspected that communication between the two receptors in breast epithelial cells might explain how estrogen and tamoxifen exert their effects - knowledge that might lead to better drugs or drug combinations to prevent breast cancer.

"The estrogen receptor enhances cell proliferation," Collins said. "That's why we give tamoxifen to women with breast cancer. If you use tamoxifen to deprive certain breast tumors of estrogen, they will regress. Retinoic acid also may cause them to regress. We think the receptors compete for a what we call a common co-activator.

"When these shared co-activators were discovered a few years ago, we wondered if cross talk existed between the estrogen receptor and the retinoic-acid receptor. We decided to see whether the activity of the retinoic-acid receptor is affected when cells are treated with estrogen or tamoxifen."

His hunch proved right when his work suggested that estrogen and tamoxifen might be exerting their effects indirectly by modulating the retinoic-acid receptor's role in halting cell proliferation.

Collins suspects that the explanation for his observation is the equivalent of a molecular seesaw. Both receptors use a shared pool of co-activator protein for activation. Whichever receptor gets to that common pool first has the winning advantage.

"When estrogen is around, the estrogen receptor uses the available co-activator, leaving little or none for the retinoic-acid receptor to carry out its role in inhibiting cell proliferation," he said. "Tamoxifen relieves this effect. We'd like to know whether anti-estrogens and retinoic acid work as effective chemopreventive agents because of their ability to activate the retinoic-acid receptor."

Adding retinoic acid to cells, Collins said, should cause its receptor to be activated at the expense of the estrogen receptor, an idea he plans to test soon.

Puzzling, revealing finding

In contrast to work with normal breast cells, treating breast cancer cells with estrogen does not result in inhibition of the retinoic-acid receptor. This finding, while puzzling, helps explain why other labs haven't observed the reciprocal interaction between the receptors, Collins said.

"Earlier studies by other labs used breast-cancer cell lines to look at possible interactions between the estrogen and retionoic-acid receptors, whereas our study used normal breast epithelial cells," he said. "The role of anti-estrogens like tamoxifen in enhancing retinoic-acid receptor activation may occur only in normal or pre-malignant cells."

Collins plans further experiments to investigate why reciprocal interaction between the receptors is disrupted in malignant cells.

"One explanation for the differences seen in cancer cells is that the gene for the retinoic-acid receptor may be deleted in tumors, which has been observed previously in breast biopsy samples. It's also possible that the co-activator is present in higher levels in cancer cells than in normal breast epithelia."

Indeed, breast cancers frequently acquire multiple copies of the gene that specifies one of the common co-activators. This enhanced co-activator expression may effectively eliminate the reciprocal interaction between the estrogen and retinoic-acid receptors.

The retinoic-acid receptor's importance in normal and leukemic blood-cell proliferation has been a focus of Collins over the last 10 years.

"The reason for studying the receptor's function in leukemic cells is that blood is so easily accessible," he said. "Tissues from solid tumors are much more difficult to access."

A wave of new cancer prevention drugs is on the horizon, Collins said, but their success depends on a comprehensive understanding of a complex disease.

"Development of new targeted therapies or chemopreventive agents - and we certainly will see more of these coming along in the next five years - has to take those factors into consideration to be effective," he said.

Help Us Eliminate Cancer

Every dollar counts. Please support lifesaving research today.


There are no tags on this page. A list of tags will appear here once there are.