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2014 BCRP Investigator Vignette

Title: A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-induced Apoptosis

Investigator: V. Craig Jordan, OBE, PhD, DSc, FMedSci; Lombardi Comprehensive Cancer Center of Georgetown University

At the moment, using this money from the Breast Cancer Research Program, we've been able to make new discoveries that will revolutionize, really research in the laboratory and clinical research in the future. We have created a new model for acquired resistance to Tamoxifen. It couldn't have been done without this grant, and it came out of all of the work we've done on estrogen-induced apoptosis. We can do things in cell culture that we used to use animals for-very important. We can design a new safe hormone replacement therapy. That will completely revolutionize women's health because now we understand how the whole of women's health with hormone replacement therapy works. So those two big things will help the next generation of investigators to move forward in women's health.

Tamoxifen was what we called a non-steroidal anti-estrogen. It blocks the estrogen fuel getting into the fire to stimulate the tumor to grow. And the one thing that we know about cancer, the longer you use a therapy, the cancer that is dividing indefinitely can find a way of defeating that block that you're trying to control the cancer. So drug resistance-acquired resistance-became the most important thing. So in the laboratory, we devised animal models and discovered the first model of acquired Tamoxifen resistance. And by a series again of lucky accidents-having bright intelligent PhD students, that's the key-we discovered that if you keep transplanting these Tamoxifen resistant tumors in animals year after year after year to this magic number of five years-remember five years is how we treat patients with Tamoxifen - so what one of my students did was give physiological estrogen to these animals because we wanted to see how growth was regulated. The tumors disappeared; absolutely melted away. He was upset, and I said, it's a discovery.

Some surgeons came to me about three or four years later and they could reproduce it; therefore, it was a real result. And this is how we discovered the new biology of estrogen-induced apoptosis, that with the help of the Department of Defense grant, there's been a major, major new finding that we can apply to medicine, and we can understand prevention better than we've ever been able to understand it before.

This is how we can view it. The cells learn to grow in a very, very fuel-deprived environment. They're just squeaking along on a little bit of fuel-estrogenic tickle-that they can pick up. Now they learn how to grow with nothing there. And now we come back with jet fuel, and we put the jet fuel, the real estrogen growth signal, into a clapped out Volkswagen and it just explodes it right there. It can't cope with this massive over-stimulation and has no choice but to die.

The Women's Health Initiative shows us that for 40 percent of the women that you're giving six years of hormone replacement-in 60 year-old women, so they've been deprived of estrogen for a long time-you give that, you stop the estrogen; those women don't get more tumors. And the recent analysis in 2012 in Lancet Oncology has shown not only did it decrease breast cancer, it decreases mortality, and women are living longer, and it stays that way even after you stop taking about six years of estrogen alone. It's killing the cancer cells just as we have found in the laboratory.

We've had a very, very good relationship with the Breast Cancer Research Program because basically, we have created an understanding where there was none. We've encouraged other investigators to answer questions when no questions were being answered. We've now seen clinical results with different eyes.

So the big question, where we're going for the future; why does the combination estrogen and progestin cause breast cancer if the estrogen alone is killing off the breast cancer? That will completely revolutionize women's health for the next century.