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

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.

Figure 1

University of Wisconsin Clinical Cancer Center faculty involved in hormone action and breast cancer therapy. Back row left to right: Dr. Gerald C. Mueller, Dr. Jack Gorski, Dr. V Craig Jordan and Dr. Douglas C. Tormey; seated left to right: Dr. Harold Rusch and Dr. Paul P. Carbone. This photograph was taken in 1984 just prior to the satellite symposium entitled “Estrogen and Antiestrogen Action: Basic and Clinical Aspects” hosted by the Cancer center in Madison as part of the events surrounding the 7^th International Congress of Endocrinology in Montreal Canada. The proceeding were published by the University of Wisconsin Press as a book under the title Estrogren/Anti-estrogen Action and Breast Cancer Therapy edited by V. Craig Jordan.

Figure 2

Molecular networks potentially influence the expression of SERM action in a target tissue. The shape of the ligands that bind to the oestrogen receptor (ERs) α and β programs the complex to become an estrogenic or anti-estrogenic signal. The context of the ER complex (ERC) can influence the expression of the response through the number of co-repressors (CoR) or co-activators (CoA). In simple terms, a site with few CoAs or high levels of CoRs might be a dominant anti-estrogenic site. However, the expression of estrogenic action is not simply the binding of the receptor complex to the promoter of the estrogen-responsive gene, but a dynamic process of CoA complex assembly and destruction. A core CoA, for example, steroid receptor coactivator protein 39 (SRC3), and the ERC are influenced by phosphorylation cascades that phosphorylate target sites on both complexes. The core CoA then assembles an activated multiprotein complex containing specific co-co-activators (CoCo) that might include p300, each of which has a specific enzymatic activity to be activated later. The CoA complex (CoAc) bind to the ERC at the estrogen-responsive gene promoter to switch on transcription. The CoCo proteins then perform methylation (Me) or acetylation (Ac) to activate dissociation of the complex. Simultaneously, ubiquitylated and destroyed in the 26S proteasome. Therefore, a regimented cycle of assembly, activation and destruction occurs on the basis of the preprogrammed ER complex. However, the co-activator, specifically SRC3, has ubiquitous action and can further modulate or amplify the ligand-activated trigger through many modulating genes that can consolidate and increase the stimulatory response of the ERC in a tissue. Therefore, the target tissue programmed to express a spectrum of responses between full estrogen action and anti-oestrogen action on the basis of the shape of the ligand and the sophistication of the tissue-modulating network. NFκB, nuclear factor κB. With permission from Nature Publishing Group, Jordan VC, Chemoprevention of Breast Cancer with Selective Estrogen Receptor Modulators, Nature Reviews Cancer, Volume 7:46–53, 2007.

Figure 3

The ladies of the UWCCC Tamoxifen Team in 1983. Far left Ethel Cormier and far right Anna T. Riegel (née Tate) both PhD students. In the center is Barbara Gosden (deceased) who spent two years in the laboratory following her MSc degree at the University of Leeds in 1979 with Anna Riegel. Mara E. Lieberman (deceased) between Barbara and Anna, joined my Team in 1981 from Jack Gorski’s Laboratory. This article is dedicated to their memory. Both were outstanding practical scientists. Mara recruited Rich Koch who performed hundreds of experiments using the isolated pituitary gland cells assay from immature mice to perform structure function relationships of SERMs that bound to the ER.

Figure 4

The Wisconsin Tamoxifen Team in the mid 1980’s. Front row left to right Simon Robinson (Post Doc from the University of Leeds), Wade Welshons (Assistant Scientist from Jack Gorski’s laboratory), Chris Parker (Estrogen Receptor Laboratory), Peter Ravdin (Medical Oncology Fellow), Rich Koch (Technician). Center (back row), Marco Gottardis, PhD Student, Right Mike Wolf (estrogen receptor laboratory), Richard Bain’s (technician metabolite analysis), Eric Phelps (summer student), Pat Mortons (Medical Illustrator for the hospital).

Figure 5

The Wisconsin Tamoxifen Team in 1991 at the Swan Hotel, Orlando, Florida. Front Row (left to right), Professor Y Iino, who visited for a year in the 1980s and subsequently ensured that the other Japanese Physicians would join my later Tamoxifen Teams). M-Wei Jeng (PhD student) and S-Y Jeng. Back row near American Flag Doug Wolf (PhD Student), John Pink (PhD Student), Craig Jordan (estrogen receptor laboratory), Delinda Mauel (radioimmuno assay), Sue Langan-Fahy (tamoxifen assays), Simon Robinson (post doc). The meeting on Long Term Tamoxifen Treatment for Breast Cancer lasted for 3 days over the 4^th of July. The University of Wisconsin published the book “Long Term Tamoxifen Treatment for Breast Cancer ed. V Craig Jordan in 1994.”