Awarded 2018 Best E-Newsletter by the National Association of Government Communicators
Internet Explorer is no longer a supported browser.

This website may not display properly with Internet Explorer. For the best experience, please use a more recent browser such as the latest versions of Google Chrome, Microsoft Edge, and/or Mozilla Firefox. Thank you.

Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

June 2016

Eighteenth year of Rodbell Lecture spotlights role of hormones in cancer

Rodbell Lecture speaker Myles Brown, M.D., has changed the way researchers think about the role of hormones in breast and prostate cancer.

Our year-long celebration of the NIEHS 50th anniversary is a great opportunity to look back at the history of the Rodbell lectures (see text box). Each year, the Dr. Martin Rodbell Lecture Series Seminar features a presentation by a scientist who has made significant contributions to a particular field of study.

The 2016 speaker, Myles Brown, M.D., has changed the way researchers think about the role of hormones in breast and prostate cancer. His May 10 talk, "Hacking the Hormone Code," was hosted by NIEHS Reproductive and Developmental Biology Laboratory Chief Kenneth Korach, Ph.D.

As a medical oncologist, Brown focuses on the prevention, diagnosis, and treatment of cancer. He believes work from his lab and others adds to the paradigm Rodbell established. Brown said he read that Rodbell’s experience as a signalman in the Navy became the impetus for his discovery of the first biochemical evidence for how certain proteins, called G-proteins, transport hormonal signals from the surface of a cell to secondary messengers inside the cell.

"Rodbell sent radio signals, and he was thinking about how cells communicate with each other," Brown said. "Much what he taught us continues to be true today, and we’ve been spending the last 30 to 40 years filling in the details."

Resistance in hormone-dependent cancers

Most of Brown’s research centers on why hormone-dependent cancers, primarily of the breast and prostate, are so responsive to steroid hormones. Steroid hormones are a class of signaling molecules that regulate organ physiology. They are part of the endocrine system and are produced in the adrenal glands, gonads, and placenta. Brown wants to understand why endocrine therapies that target these hormones or their receptors work in some patients but not in others. In some cases, patients initially respond to therapy, then develop resistance.

Brown said that within the last few years, several groups have studied individuals with breast cancers that have relapsed following endocrine therapy. The findings indicated that mutations in these cancers cluster in a part of the estrogen receptor (ER) called the ligand-binding domain. This section of the ER binds the steroid estradiol and is responsible for sending the strongest transcriptional signal.

A member of Brown’s group found that one of the mutations, known as Y537C, is the most common resistance mutation in patients with such relapses. The result appears to answer the question of how resistance develops in some patients, and it provides a basis for the development of a pharmaceutical compound that targets the mutation.

"We found it in about 17 percent in our cohort, but using more sensitive techniques, others are finding it in 25 to 30 percent of patients," Brown said. "I think it’s strong evidence that in at least a third of those tumors, the cancer cells are ER+ and depend on the presence of the mutation."

Cancer-causing mutations in prostate cancer

According to Brown, other scientists have identified recurrent mutations in a protein called SPOP, in prostate cancer. The prevailing theory among prostate cancer scientists is that SPOP stabilizes a group of proteins involved in DNA repair and cell signaling. Mutations in SPOP remove the scaffolding from these important molecules, setting prostate cells on a path to cancer.

Proteomic studies found several targets of SPOP. One of those targets, a gene called TRIM24, promotes the growth of prostate cancer cells. By removing TRIM24 in castration-resistant prostate cancer cell lines, Brown was able to slow the growth of the cancer. Although medicines that more effectively block the effect of androgen, a hormone that promotes the development of male sex characteristics, have been approved for castration-resistant prostate cancer, patients almost invariably relapse. Brown believes compounds that target TRIM24 could be developed.

Brown’s seminar engaged the audience, especially Korach, a trained endocrinologist. "Myles Brown was a perfect choice as the 2016 Rodbell lecturer, since he exemplifies the same outstanding research and insights as Marty Rodbell," he said.


NIEHS marks 18th year of Rodbell lectures

By Eddy Ball

Since 1998, the selection of a scientist to present a talk in the Dr. Martin Rodbell Lecture Series has marked a special recognition for chemists and molecular biologists at the leading edge of their fields.

The series honors former NIEHS Scientific Director Martin Rodbell, Ph.D.(https://www.niehs.nih.gov/about/highlights/nobel/), a 1994 Nobel laureate who gave the first talk in 1998, just weeks before his death. Rodbell was the first of four Nobel winners to speak in the series. All Rodbell lecturers are men and women with outstanding achievements, innovative research, and some of the highest scientific honors, including the National Medal of Science and election as fellows in the American Academy of Arts and Sciences.

The 1994 Nobel Prize in Physiology or Medicine was awarded jointly to Rodbell and Alfred Gilman, M.D., Ph.D., "for their discovery of G-proteins and the role of these proteins in signal transduction in cells." The work Rodbell and Gilman conducted over several decades culminated in a new, more complex theory that led to a revolution in thinking about hormone signaling. Their approach upset what Rodbell described in 1980 as “the classical notion of receptor alone controlling the events related to hormone and neurotransmitter action.”

Rodbell provided evidence for additional G-proteins at the cell receptor that could inhibit and activate transduction, often at the same time. G-proteins thus proved to be the essential components of the hormone signaling process. Subsequent work demonstrated that aberrations in G-proteins affect their role in several functions, including cell growth and neurotransmission, and underlie a wide variety of disease states, from cancer to cholera.

Citation: Rodbell M. 1980. The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature 284(5751):17-22. Full text.

Back To Top