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A CENTURY OF DECIPHERING
THE CONTROL MECHANISMS OF
ESTROGEN ACTION IN BREAST CANCER:
THE ORIGINS OF TARGETED THERAPY
AND CHEMOPREVENTION
V. Craig Jordan
Abstract
The story of deciphering the mechanisms that control the growth of sex-hormone-dependent cancers started more than a hundred years ago. Clinical observations of the apparently random responsiveness of breast cancer to endocrine ablation (hormonal withdrawal) provoked scientific enquiry in the laboratory that resulted in the development of effective strategies for targeting therapy to the estrogen receptor (ER) (or the androgen receptor in the case of prostate cancer), the development of antihormonal treatments that dramatically enhanced patient survival, and the first successful testing of agents to reduce the risk of developing any cancer. Most importantly, elucidating the receptor-mediated mechanisms of sex-steroid-dependent growth and the clinical success of antihormones has had broad implications for medicinal chemistry with the synthesis of new selective hormone receptor modulators for numerous clinical applications. Indeed, the successful translational research on the ER was the catalyst for the current strategy for developing targeted therapies for the tumor and the start of “individualized medicine.” Over the past 50 years, ideas about the value of antihormones have translated effectively from the laboratory to improvement of clinical care, increase in national survival rates and significant reduction in the burden of cancer.
Keywords: Breast Cancer; Estrogen Receptor; Tamoxifen; Antiestrogen; Selective Estrogen Receptor Modulators; Antiandrogens; Prostate Cancer.
BEGINNINGS AT THE DAWN OF THE 20TH CENTURY
Schinzinger1 is credited with suggesting that oophorectomy could be used to treat breast cancer; however, this suggestion does not appear to have been adopted. In contrast, the report by Beatson2 that oophorectomy could initiate a regression of metastatic breast cancer in two premenopausal women was a landmark achievement. Although it is often stated that Beaston’s work was empirical clinical research, the rationale for conducting an oophorectomy was, in fact, an example of early translational research. Beaston was aware of the essential role of removing the ovary in maximizing milk production in cows. He reasoned that there was potentially some factor that traveled in the blood supply to the breast as there was no known connection through the nerves. Interestingly enough, he also conducted laboratory experiments on rabbits before his clinical experiment, so the work was bench-to-bedside.2 By 1900, Boyd3 had assembled the results of all the available clinical cases of oophorectomy to treat breast cancer in Great Britain in perhaps the first “clinical trial.” He concluded that only a third of metastatic breast tumors responded to oophorectomy. This clinical result and overall response rate has remained the same to this day.
Unfortunately, responses were of limited duration and enthusiasm waned as to whether this approach was the answer for cancer treatment. Also, the approach of endocrine ablation was relevant only to breast cancer (and subsequently prostate cancer4); thus, the approach was effective only in a small subset of cases of all cancer types. At the dawn of the 20th century, there was no understanding of the endocrine system or hormones. Nevertheless, laboratory studies started to decipher the biological control mechanisms responsible for the clinical observations.
LINKS BETWEEN SEX STEROIDS AND CANCER
The fashion in breast cancer research in the early years of the 20th century was to use inbred strains of mice to study the growth and incidence of spontaneous mammary cancer. Lathrop and Loeb5 found that before three months of age was the optimal time for oophorectomy to prevent the development of mammary cancer, but obviously this knowledge could not be translated to the clinical setting: who would one treat? The mechanism was also unknown until Allen and Doisy,6 using an ovariectomized mouse vaginal cornification assay, demonstrated that a principle, which they called estrogen (identified as estrone, the principal steroid), was present in ovarian follicular fluid. Their major advance set the scene for the subsequent breakthroughs in molecular endocrinology and therapeutics in the latter half of the 20th century (Fig. 1).
Figure 1. Timeline of the major landmarks in estrogen action and its application for the treatment and prevention of breast cancer.
The idea that breast cancer might be a preventable disease was extended by Professor Antoine Lacassagne, who first demonstrated that estrogen could induce mammary tumors in mice.7,8 Lacassagne9 hypothesized: “If one accepts the consideration of adenocarcinoma of the breast as the consequence of a special hereditary sensibility to the proliferative action of oestrone, one is led to imagine a therapeutic preventive for subjects predisposed by their heredity to this cancer. It would consist — perhaps in the very near future when the knowledge and use of hormones will be better understood — in the suitable use of a hormone, antagonistic or excretory, to prevent the stagnation of oestrone in the ducts of the breasts.” However, when Lacassagne stated his vision at the annual meeting of the American Association for Cancer Research (Boston) in 1936, there were no lead compounds that antagonized estrogen action but the Allen Doisy mouse assay could be used to study structure–activity relationships so as to find synthetic estrogens. Within a decade, a landmark discovery was to occur in “chemical therapy,” which was to expand the treatment of metastatic breast cancer to include postmenopausal women, who are in fact the majority who develop metastatic disease.
During the 1930s there were significant advances in the knowledge of the precise structural requirements for estrogen action in its target tissue, the vagina. Synthetic compounds based on stilbene10,11 and triphenylethylene12 were screened using the Allen Doisy ovariectomized mouse vaginal cornification assay to define compounds with optimal structures and duration of estrogen action. Sir Alexander Haddow found that carcinogenic polycyclic hydrocarbons would cause tumor regression in animals. However, they could not be used to treat humans. The nonsteroidal triphenylethylene-based estrogens had structures similar to those of polycyclic hydrocarbons and also caused tumor regression in animals. With this clue, Alexander Haddow used the first chemical therapy to treat patients. His results, published in 1944,13 demonstrated that high dose estrogen therapy was effective in causing tumor regression in postmenopausal patients with breast cancer and men with prostate cancer. There was, however, no understanding of a mechanism. Indeed, he stated in 1970: “In spite of the extremely limited practicability of such a measure [high dose estrogen], the extraordinary extent of tumor regression observed in perhaps 1% of postmenopausal cases has always been regarded as of major theoretical importance, and it is a matter for some disappointment that so much of the underlying mechanisms continues to elude us.”14 These experimental data were also a paradox, as endocrine ablation to remove estrogens and their precursors was the dogma of the time.15
In the past 50 years, the progress in deciphering the control mechanisms of estrogen action in breast cancer (and androgen action in prostate cancer) has accelerated with advances in technology and an understanding of cell biology. However, progress in research does not occur in straight lines but chance observations can create a major breakthrough. This has happened repeatedly in the story of the treatment and prevention of breast cancer.
CONCEPTUAL PROGRESS THROUGH SCIENTIFIC SERENDIPITY
It is perhaps relevant to illustrate a few astute observations by scientists that immensely accelerated progress in deciphering the complexities of hormone action and the control of breast cancer growth.
Sir Charles Dodds is credited with the syn...
