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The SERM Saga, Something from Nothing: American Cancer Society/SSO Basic Science Lecture

  • Breast Oncology
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Abstract

Background

The discovery of nonsteroidal antiestrogens created a new group of medicines looking for an application; however, at the time, cytotoxic chemotherapy was the modality of choice to treat all cancers. Antiestrogens were orphan drugs until 1971, with the passing of the National Cancer Act. This enabled laboratory innovations to aid patient care.

Methods

This article traces the strategic application of tamoxifen to treat breast cancer by targeting the estrogen receptor (ER), deploying long-term adjuvant tamoxifen therapy, and becoming the first chemopreventive for any cancer. Laboratory discoveries from the University of Wisconsin Comprehensive Cancer Center (UWCCC) are described that address a broad range of biological issues with tamoxifen. These translated to improvements in clinical care.

Results

Tamoxifen was studied extensively at UWCCC in the 1980s for the development of acquired resistance to long-term therapy. Additionally, the long-term metabolism of tamoxifen and regulation of growth factors were also studied. A concern with tamoxifen use for chemoprevention was that an antiestrogen would increase bone loss and atherosclerosis. Laboratory studies with tamoxifen and keoxifene (subsequently named raloxifene) demonstrated that ‘nonsteroidal antiestrogens’ maintained bone density, and this translated into successful clinical trials with tamoxifen at UWCCC. However, tamoxifen also increased endometrial cancer growth; this discovery in the laboratory translated into changes in clinical care. Selective estrogen receptor modulators (SERMs) were born at UWCCC.

Conclusions

There are now five US FDA-approved SERMs, all with discovery origins at UWCCC. Women’s health was revolutionized as SERMs have the ability to treat multiple diseases by switching target sites around a woman’s body on or off.

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Acknowledgment

This article is dedicated to members of the University of Wisconsin Tamoxifen Team. The question can be asked ‘What was achieved for the team members during 1980–1995’? My Ph.D. student Anna C. Riegel (née Tate) and I arrived in 1980 to build a research program that did not exist. During the 15-year period, the tamoxifen team never exceeded two dozen students and staff. In 1983, I inherited the Directorship of the steroid receptor laboratory for Southern Wisconsin, including its six staff. This was a daunting prospect so I called my mentor, the late Dr. Bill McGuire, in San Antonio to express my uncertainty at the challenge ahead. He explained that I was looking at this incorrectly. ‘This was an opportunity’ and I should treat it as such. He was absolutely correct. During the whole of this period, I had stable funding from National Institutes of Health (NIH) grants and pharmaceutical contracts, as well as philanthropic donations to the laboratory. I was promoted to Professor of Human Oncology and Pharmacology in 1985 and appointed Director of the Breast Cancer Research and Treatment Program at the University of Wisconsin Comprehensive Cancer Center in 1987. Ten Ph.D. students successfully received their degrees and publications flowed: refereed research papers (146), invited refereed reviews (22), editorials (11), book chapters (91), books edited (2), and international meetings organized (2). Members of the Wisconsin Tamoxifen Team are show in Figs. 3, 4 and 5. I would like to thank the benefactors of the Dallas/Fort Worth Living Legend Chair of Cancer Research, George and Barbara Bush Endowment for Cancer Research, and the Cancer Center Support Grant P30-CA16672 (Peter Pisters).

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  1. Dallas/Fort Worth Living Legend Chair of Cancer Research, Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    V. Craig Jordan OBE, PhD, DSc, FMedSci, FAACR

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  1. V. Craig Jordan OBE, PhD, DSc, FMedSci, FAACR
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Correspondence to V. Craig Jordan OBE, PhD, DSc, FMedSci, FAACR.

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Jordan, V.C. The SERM Saga, Something from Nothing: American Cancer Society/SSO Basic Science Lecture. Ann Surg Oncol 26, 1981–1990 (2019). https://doi.org/10.1245/s10434-019-07291-1

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