Jennifer Richer, PhD, investigator at the University of Colorado Cancer Center and assistant professor of pathology at the University of Colorado School of Medicine

In this every-second-Thursday “Decoding Cancer” series in Target Cancer, and in honor of National Breast Cancer month, Jennifer Richer, PhD, investigator at the University of Colorado Cancer Center and assistant professor of pathology at the University of Colorado School of Medicine, describes recent breakthroughs in our understanding of androgen (not estrogen!) in the growth of breast cancer. The Richer Lab’s work with androgen-mediated breast cancer offers hope of new treatments for patients with triple-negative breast cancers, which due to their lack of hormone target, currently carry the worst prognosis.


The danger and promise of hormone-driven cancers

In healthy bodies, the hormone estrogen helps breasts grow. And unfortunately, this is true of many breast cancers as well – when an estrogen-receptor-positive (ER+) breast cancer grabs estrogen from the blood, it grows.

This kick-starting of growth sounds bad, but in fact a tumor’s estrogen dependence also provides a target for its destruction. Drugs like tamoxifen compete with estrogen for these receptors – if tamoxifen plugs the keyholes meant for estrogen, the cancer cell just sits there and eventually dies off.

Similar is true for the receptors for the hormone progesterone and a receptor called HER2, which responds to growth factors – 80 percent of breast cancers depend on hormones and growth factors to grow, and so to a great extent, nixing these goodies also nixes the breast cancer. For that reason, a common first test for breast cancer patients is for estrogen and progesterone receptors and Her2.

No hormone receptors, no targets

Traditionally, the triple negative breast cancers without these three receptors have had a much worse prognosis – because they don’t depend on estrogen or the like, cutting off the “goodies” does no good.

Working at the University of Colorado Cancer Center, Jennifer Richer, PhD, hopes to add an arrow to the quiver of hormones that allow doctors to target some kinds of triple-negative breast cancer.

“Women have androgens as well as estrogen,” says Richer, one example of which is the male sex hormone testosterone. And, in fact, in postmenopausal women whose ovaries have stopped producing estrogen, the main source of estrogen in the body is from fat cells that convert androgens into estrogens.

A new class of drugs for estrogen-positive (ER+) breast cancers called aromatase inhibitors blocks this conversion, keeping estrogen levels extremely low in postmenopausal women.

An aromatase inhibitor is a nice arrow to have in the treatment quiver, partly due to its effectiveness with postmenopausal women and partly due to cancer’s insidious ability to mutate around the roadblock of tamoxifen. Frequently at about the five-year point of being on tamoxifen, cancer learns to circumvent it and the drug’s effectiveness wanes. An aromatase inhibitor is a strong second line of defense.

But then, having blocked the conversion of testosterone to estrogen, “a patient has a slightly elevated level of circulating androgens,” Richer says.

Breast cancer becomes prostate cancer

The question now is, what does this slightly elevated level of androgen do in women – and does it provoke or appease breast cancer?

Well, in many ways prostate cancer is to men what breast cancer is to women – just like estrogen tells some breast cancers to grow, so too do the androgens tell some prostate cancers to grow.

And just as the widely used drug tamoxifen blocks the action of estrogen in breast cancer, the widely used drug casodex blocks the action of androgens like testosterone and thus the proliferation of androgen-driven prostate cancers.

Researchers like Richer think that some breast cancers that overcome their dependence on estrogen to blast past tamoxifen do it by picking up a new addiction to androgen – in this case, a woman’s breast cancer may start acting like a man’s prostate cancer in its dependence on androgens as its hormone of choice. (And now we’re on the cutting edge of what science does and doesn’t know for sure.)

Could you treat these androgen-dependent breast cancers with an androgen blocker, as in prostate cancer?

“In the past couple years, two big studies have come out that show that around 30 percent of triple-negative breast cancers have the androgen receptor,” Richer says. “In these triple-negative breast cancers, you can’t target estrogen receptors, but maybe you can target androgen receptors.”

So now the question is, for estrogen receptor-positive breast cancers that have swapped their dependence, and for the 30-40 percent of triple-negative breast cancers that are androgen-receptor-positive, why not hit them with the anti-androgen casodex?

Targeting androgen-positive breast cancers

The first step in answering a question like this is to kick the tires in the lab, before ever road-testing it with humans. And so Dawn Cochrane, PhD, instructor in the Richer Lab, treated breast cancer cells lines with both casodex and a new anti-androgen drug MDV-3100,developed by Dr. Charles Sawyers at Memorial-Sloan Kettering and is currently in phase III clinical trials for treatment of prostate cancer.

“Interestingly not only did MDV-3100 completely abolish androgen-mediated breast cancer, but it stopped estrogen-mediated breast cancer proliferation, as well,” Richer says.

This was true despite the fact that MDV-3100 only binds to androgen receptors and not estrogen receptors. And casodex? Well, while it brought its prostate cancer bag of tricks to bear on androgen-driven breast cancer, on the other hand it augmented the growth of estrogen-driven breast cancer cells. So while casodex may someday prove useful for patients with androgen – but not estrogen! – driven cancers, MDV-3100 is a promising intervention for the many breast cancer patients who have both receptors.

In fact, Richer and CU Cancer Center colleague, Anthony Elias, MD, professor of medical oncology at the University of Colorado School of Medicine, are in talks with MDV-3100’s parent companies, Medivation and Astellas Pharma to develop a clinical trial of the drug with breast cancer patients.

But the moral of this convoluted scientific tale is that in the story of hormone-dependent breast cancers, there are certainly more characters than the big three originally thought. Also, these characters interact in wild and sometimes unexpected ways.

“Now our theory that we’re testing in the lab is that estrogen and androgen receptors work together, normally and in cancer,” Richer says. The surprising results of MDV-3100 and casodex in estrogen-positive and androgen-positive breast cancers implies that perhaps affecting one receptor affects the others, in ways never before imagined.

Richer hopes to soon understand these characters. By defining the interactions of estrogen, progesterone, HER2, and now androgen, Richer could soon add treatment options for cancers with multiple receptors. More importantly, her work with androgen may offer a first treatment for many of the less common, but more aggressive, triple-negative breast cancers.