Jensen wins Lasker for research on estrogen receptors

The 2004 Lasker Award for Basic Medical Research has been presented to Elwood Jensen, the Charles B. Huggins Distinguished Service Professor Emeritus in the Ben May Institute for Cancer Research. Jensen is one of three scientists whose discoveries “revolutionized the fields of endocrinology and metabolism,” according to the award citation. Jensen’s work had a rapid, direct and lasting impact on treatment and prevention of breast cancer.

The Lasker Awards are the nation’s most distinguished honor for outstanding contributions to basic and clinical medical research. Often called “America’s Nobel,” the Lasker Award has been awarded to 68 scientists who subsequently went on to receive the Nobel Prize, including 15 in the past 10 years.

Jensen will share the basic medical research award with two colleagues, Pierre Chambon of the Institute of Genetics and Molecular and Cellular Biology (Strasbourg, France) and Ronald Evans of the Salk Institute for Biological Studies (La Jolla, California) and the Howard Hughes Medical Institute.

They were selected for their discovery of the “superfamily of nuclear hormone receptors and the elucidation of a unifying mechanism that regulates embryonic development and diverse metabolic pathways.” The implications of this research for understanding human disease and accelerating drug discovery “have been profound and hold much promise for the future,” noted the announcement from the Lasker Foundation.

Jensen, 84, is being honored for his pioneering research on how steroid hormones, such as estrogen, exert their influence. His discoveries explained how these hormones work, which has led to the development of drugs that can enhance or inhibit the process.

“It feels wonderful,” Jensen said when asked about receiving the award. “It came as a complete surprise. I don’t even know who nominated me.”

Hormones control a vast array of biological processes, including embryonic development, growth rate and body weight. Before Jensen’s research, however, the way in which hormones cause these effects was “a complete mystery,” recalled Gene DeSombre, Professor Emeritus in the Ben May Institute for Cancer Research, who worked with Jensen as a post-doctoral fellow and then as his colleague.

In the 1950s, biochemists thought a hormone entered a cell, where a series of oxidation and reductions reactions with the estrogen provided needed energy for the growth stimulation and other specific actions shown by estrogens.

From the late 1950s to the 1970s, Jensen entirely overturned that notion. Working with estrogen, he proved that hormones do not undergo chemical change. Instead, they bind to a receptor protein within the cell. This hormone-receptor complex then travels to the cell nucleus, where it regulates gene expression.

At the time, this idea was heresy. “That really got him into some hot water,” recalled DeSombre. “Jensen struggled quite a lot,” echoed Shutsung Liao, another Ben May Institute colleague, who subsequently found a similar system for testosterone action. But for Jensen, just getting into hot water was a struggle. When he first presented preliminary data at a 1958 meeting in Vienna, only five people attended, three of whom were the other speakers. More than 1,000 attended a simultaneous symposium on the metabolic processing of estrogen.

In the next 20 years, Jensen convinced his colleagues by publishing a series of major and highly original discoveries in four related areas of hormone research:

Jensen discovered the estrogen receptor, the first receptor found for any hormone. In 1958, using a radioactive marker, he showed that only the tissues that respond to estrogen, such as those of the female reproductive tract, were able to concentrate injected estrogen from the blood. This specific uptake suggested that these cells must contain binding proteins, which he called “estrogen receptors.”

In 1967, Jensen and Jack Gorski of the University of Wisconsin showed that these putative receptors were macromolecules that could be extracted from these tissues. With this method, Jensen showed that when estrogen bound to this receptor, the compound then migrated to the nucleus where it bound avidly and activated specific genes, stimulating new RNA synthesis.

By 1968, Jensen had devised a reliable test for the presence of estrogen receptors in breast cancer cells. It had been known for decades that about one-third of premenopausal women who had advanced breast cancer would respond to estrogen blockade brought about by removing their ovaries, the source of estrogen, but there was no way to predict which women would respond. In 1971, Jensen showed that women with receptor-rich breast cancers often have remissions following removal of the sources of estrogen, but cancers that contain few or no estrogen receptors do not respond to estrogen-blocking therapy.

By 1977, Jensen and Geoffrey Greene, also in the University’s Ben May Institute, had developed monoclonal antibodies directed against estrogen receptors, which enabled them to quickly and accurately detect and count estrogen receptors in breast and other tumors. By 1980, this test had become a standard part of care for breast cancer patients.

This work “transformed the treatment of breast cancer patients,” noted the Lasker Foundation, “and saves or prolongs more than a 100,000 lives annually.”

“Jensen’s revolutionary discovery of estrogen receptors is beyond doubt one of the major achievements in biochemical endocrinology of our time,” said DeSombre. “His work is hallmarked by great technical ingenuity and conceptual novelty. His promulgation of simple yet profound ideas concerning the role of receptors in estrogen action have been of the greatest importance for research on the basic and clinical physiology, not only of estrogens, but also of all other categories of steroid hormones.”

By the early 1970s, Jensen was searching for chemical, rather than surgical, ways to shield estrogen-dependent tumors from circulating hormones. He and colleague Craig Jordan (then at the Worcester Foundation for Experimental Biology in Massachusetts) subsequently found that women with cancers that contain large amounts of estrogen receptors also are likely to benefit from tamoxifen, a compound that blocks some of the effects of estrogen. Patients with few or no receptors could immediately move on to chemotherapy rather than waiting months to find out that the tumors were growing, despite tamoxifen treatment.

“We were glad we could do something that helped patients with breast cancer,” Jensen recalled, “to know that our basic research findings could be extended to the clinical management of patients with this terrible disease.”

Following Jensen’s lead, researchers soon found that the receptors for the other major steroid hormones, such as testosterone, progesterone and cortisone, worked essentially the same way.

In 1986, Pierre Chambon and Ronald Evans separately, but simultaneously, discovered that the steroid hormone receptors were merely the tip of the iceberg of what would turn out to be a large family of structurally related nuclear receptors, now known to consist of 48 members. Evans and Chambon unearthed a number of these receptors, which revealed new regulatory systems that control the body’s response to essential nutrients (such as Vitamin A), fat-soluble signaling molecules (such as fatty acids and bile acids), and drugs (such as the glitazones used to treat Type 2 diabetes and retinoic acid for certain forms of acute leukemia).

These three individuals “created the field of nuclear hormone receptor research, which now occupies a large area of biological and medical investigation,” said Joseph Goldstein, chairman of the international jury of researchers that selects recipients of the Lasker Awards, and a recipient of the Lasker Award for Basic Medical Research and the Nobel Prize in Medicine in 1985.

Jensen, known for concluding his lectures in verse, neatly summed up what his extraordinary series of discoveries might mean to a woman who has been diagnosed with breast cancer:

“A lady with growth
neoplastic
Thought surgical ablation too drastic.
She preferred that her ill
Could be cured with a pill,
Which today is no longer
fantastic.”

The Lasker Awards were presented at a ceremony Friday, Oct. 1, in New York City.

The Lasker Foundation presented the Award for Special Achievement in Medical Science to bioterrorism expert Matthew Meselson (A.B.,’51; honorary Ph.D,’75) of Harvard University, who received the honor for a lifetime career that “combines penetrating discovery in molecular biology with creative leadership in public policy aimed at eliminating chemical and biological weapons.”

The Lasker Awards, first presented in 1946, are administered by the Albert & Mary Lasker Foundation. The late Mary Lasker is widely recognized for her singular contribution to the growth of the National Institutes of Health and her commitment to government funding of medical research in the hope of curing devastating diseases.

Lasker Award recipients receive an honorarium, a citation highlighting their achievements, and an inscribed statuette of the Winged Victory of Samothrace, the Albert and Mary Lasker Foundation’s traditional symbol representing humanity’s victory over disability, disease and death.

Many University faculty members and alumni have received the Lasker Award in the past, including: George Wells Beadle, the William E. Wrather Distinguished Service Professor Emeritus in Biology and the College, who won the Lasker in 1950 and the Nobel in 1958; Charles Huggins, the William B. Ogden Distinguished Service Professor in Surgery, who won the Lasker in 1963 and the Nobel in 1966; Roger Sperry (Ph.D.,’41), who won the Lasker in 1979 and the Nobel in 1981; James Watson (S.B.,’47), who won the Lasker in 1960 and the Nobel in 1962; and Janet Rowley, the Blum-Riese Distinguished Service Professor in Medicine and Genetics & Cell Biology, who won the Lasker in 1998.