David T. Zava

Hormones in breast cancer: Update 1978☆

The role of cytoplasmic estrogen receptor (ER) assays in determining therapeutic strategies for advanced breast cancer is certainly well established. The use of ER assays in the primary breast tumor specimen to predict for early recurrence and ultimate survival is a new finding, however, and will probably be employed in future trials of adjuvant therapy. The prevalence and significance of nuclear-bound ER still requires additional clarification. Our previous suggestion that progesterone receptor measurements might be a useful marker for hormone dependence in advanced breast cancer is gaining support and may soon have a place in routine therapeutic decision-making. The emphasis on early adjuvant therapy has hastened the search for a safe endocrine therapy that would have good patient compliance and achieve remission rates comparable to previous agents and procedures. Antiestrogens show promise of meeting these requirements. We are now beginning an era in which primary and secondary systemic therapies for breast cancer can be based on sound biologic principles. The empirical approach is outdated.

Progesterone interaction with estrogen and antiestrogen in the rat uterus — receptor effects

Daily injections of estradiol or the antiestrogen tamoxifen initially stimulate uterine weight increase and progesterone receptor synthesis, though continued tamoxifen fails to maintain the increased weight. The stimulatory actions of both estradiol and tamoxifen are inhibited or reversed by a single injection of progesterone. It has been hypothesized that progesterone antagonizes estrogen action by reducing estrogen receptor levels, but in the present experiments neither cytoplasmic nor nuclear estrogen receptor was affected. We conclude that progesterone acts at a point beyond estrogen receptor availability or translocation to antagonize estrogen action.

Estrogen and progestin receptors in meningiomas: clinicopathological correlations.

Estradiol and progesterone receptors were studied in 44 patients with meningiomas and correlated to the clinicopathological features and amount of preoperative corticosteroid therapy. Thirty-four (77%) of the meningiomas contained high tilers of specific high-affinity cytosol [3H]promegestone (R 5020) binding sites (mean 2,902 fmol/g tumor; range 0–9,598 fmol/g tumor) whereas only minuscule amounts of a nonspecific cytoplasmic [3H]estradiol binding component (mean 48 fmol/g tumor; range 0–201 fmol/g tumor) were detectable. No nuclear binding activity for [3H]estradiol was demonstrable. There was no convincing correlation between high PR activity and the age, sex, or menopausal status of the patients. The correlation study between the amount of preoperative corticosteroid therapy with the amount of [3H]promegestone binding revealed no dose relationship. Correlating [3H]promegestone content with the histologic type, we found 96% of meningothelial, 71% of transitional, and 40% of fibroplastic; meningiomas to contain progesterone receptors. The necessity of in vitro studies is stressed to assess the biosynthesis and biological activity of the progesterone receptor in meningiomas, which is apparently not estrogen regulated, as is the case in other estrogen target tissues.

Biological expression of steroid hormone receptors in primary meningioma cells in monolayer culture.

Primary meningiomas have been grown in monolayer culture and tested for the presence of steroid hormone receptors and sensitivity to various steroids and steroid antagonists. None of the 10 solid tumors or the primary cultures derived from them contained estrogen receptors, either in the cytoplasm or in the nucleus. Progesterone receptors were present in 50–70% of the solid tumors and some of the primary cultures. Four of four and five of five primary cultures contained, respectively, androgen and glucocorticoid receptors. When one of the primary cultures was tested for growth sensitivity to estrogen, tamoxifen, progesterone, hydrocortisone, and dihydrotestosterone, the last two had noticeable stimulatory effects on growth by day 5. Interestingly, only androgen and glucocorticoid receptors were present in the primary tumor cells in culture, suggesting that these receptors mediated the effects of their respective hormones on growth.

A physiological role for estrogen and progesterone in breast cancer

Abstract Breast cancer is often hormone responsive, since growth or regression of tumors can often be modulated by appropriate endocrine manipulations. Estrogen and progesterone are major hormones involved in regulation of breast cancer tumor growth. Considerable insight into the mechanism of action of these hormones on tumor growth stimulation has been provided by demonstration of specific receptors for each. The inference that each hormone acts independently through its receptor to control tumor growth is belied by current studies which show that certain hormones are capable of regulating the receptor sites, metabolism, or nuclear translocation of others. This may begin to explain the complex hormonal interactions and requirements of normal and neoplastic breast tissues. Considerable progress has thus been made in understanding the basis for success of various ablative therapies. The pharmacologie actions of estrogens and progestins in causing breast tumor regression is much less well understood. The role of hormone receptor sites has not been established in the mechanism of tumor regression caused by these pharmacological therapies. Nevertheless, when estrogen receptors are absent in a tumor, we can with accuracy pre.dict that endocrine therapies will fail, whereas when ER is present the likelihood of a successful response to pharmacological or ablative therapy is high. Receptor sites seem to be a common denominator and useful marker for hormone dependence or hormone responsiveness, irrespective of their actual role in the tumor regression process. Further investigations into the receptor functions should lead to new approaches in the endocrine management of patients with breast cancer.

Hormones and Their Receptors in Breast Cancer

Publisher Summary This chapter describes normal target tissues including mammary gland, which contain specific receptors for hormones: (1) cytoplasmic proteins for the steroid and (2) cell-surface receptors for polypeptides. These receptor sites are responsible for the initial interaction between the hormone and the cell and function to trigger the biochemical chain of events characteristic for the particular hormone. Estrogen acts directly on the normal mammary gland to promote growth and differentiation. However, estrogen also stimulates the release of pituitary prolactin, which likewise acts upon the mammary cell. At present, there are several procedures for measurement of estrogen (ER) in cytosols of target tissues. The receptor can be quantitated by demonstration of specific 8 S and 4 S binding of [3H] estradiol on sucrose density gradients (SDG). The dextran-coated-charcoal method (DCC) is equally quantitative and less expensive. Non-receptor-bound [3H] estradiol is removed from specific estradiol-bound receptor by charcoal. In castrated premenopausal or in postmenopausal breast cancer patients, estrogen precursors are secreted by the adrenal gland and converted to estrogens by peripheral tissues.

Steroid Receptors in Breast Tumors—Current Status

Publisher Summary This chapter reviews the role of several hormones and their receptors in breast cancer tissues and examines mechanisms of control. Breast cancer is often hormone-responsive because growth or regression of tumors can often be modulated by appropriate endocrine manipulations. Estrogen and progesterone appear to be the major hormones involved in the regulation of breast tumor growth. The inference that each hormone acts independently through its receptor to control tumor growth is belied by the current studies showing that certain hormones are capable of regulating the receptor sites, metabolism, or nuclear translocation of others. This may begin to explain the complex hormonal interactions and the requirements of normal and neoplastic breast tissues. Considerable progress has, thus, been made in understanding the basis for success of various ablative therapies. Many of the studies on hormone-dependent breast carcinoma employ animal models, particularly carcinogen-induced rat mammary tumors, which regress after endocrine ablative surgery. The chapter discusses the relevance of these animal models to the clinical problem of human breast cancer. It illustrates the physiological principles of hormone action in breast cancer tissue so that an appreciation of the mechanism of endocrine-induced breast tumor regression will develop. Such an understanding should lead to a more rational approach for selecting or rejecting endocrine therapy for advanced breast cancer patients.

Receptors and breast cancer: Do we know it all?

Abstract The use of cytoplasmic estrogen receptor to predict endocrine responsiveness in breast cancer patients is now well established. It is our contention that this pertinent clinical application is only the first of many contributions from receptor studies to the clinic. Efforts are now underway to examine the distribution of receptors within tumor cells, and in particular the significance of receptors in tumor nuclei in the absence of hormone. Also, the demonstration of a direct stimulation of progesterone receptor synthesis by estradiol in cultured breast tumor cells now permits a careful dissection of the complete estrogen response system which should provide clues to the mechanism of antiestrogen action in causing tumor regression. Finally, it is now evident that pharmacologic effects of steroids in breast cancer may be mediated through different pathways than expected from studies of normal physiology.

Steroid-nucleoside interactions with receptors.

Abstract Steroidal pyrimidines (steroid-nucleosides) have been suggested as potential agents for cancer chemotherapy. In order to evaluate the notion that the steroid moiety of such agents provides organ specificity, a series of steroid-nucleosides have been evaluated for their steroid binding properties. The 21-substituted progesterone derivatives showed affinity for androgen receptor whereas some of the 21-substituted corticoids exhibited affinity for glucocorticoid receptor. None of the 3- or 21-substituted steroids showed significant binding to estrogen or progesterone receptor.

Chapter 23 Methods for Assessing the Binding of Steroid Hormones in Nuclei

Publisher Summary This chapter describes the methods for assessing the binding of steroid hormones in nuclei. When a steroid hormone enters a target cell, it binds to a receptor molecule that is then translocated into the nucleus. There it associates with nuclear sites and stimulates a sequence of events resulting in a series of biological responses. The binding of receptor-steroid complexes by nuclei can be studied by several methods. A radioactive steroid can be administered to intact animals or to cell or organ cultures, the nuclei isolated, and the content of radioactivity then measured directly. Nuclei can be isolated from cells and then incubated with radioactive receptor–steroid complexes prepared independently. Nuclei can be isolated and the receptor–steroid complexes measured by incubation with an excess of radioactive steroid at an elevated temperature permitting exchange with the unlabeled steroid. The difficulty of this assay is the technical problem of high nonspecific steroid binding in nuclei of tissues. To circumvent this problem, an alternative nuclear exchange assay is discussed in the chapter. Some of the methods developed and used to examine the binding of steroid receptors to isolated nuclei are also discussed.