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Gerard A Tarulli, Lisa M Butler, Wayne D Tilley and Theresa E Hickey

While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

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W R Miller

Both mammary adipose tissue and breast cancers have the ability to aromatize androgens into oestrogens. Such potential may maintain the growth of hormone-dependent tumours. It has therefore been important to determine the effects of new aromatase inhibitors such as formestane, exemestane, anastrozole and letrozole on oestrogen biosynthesis and concentrations of endogenous hormones within the breast. Studies based on in vitro incubations of breast cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50 nM (although the relative efficacy varies between tissues and test systems). Despite this potential, in vitro incubations of breast tissues from patients treated with type II inhibitors such as aminoglutethimide and letrozole can display paradoxically high aromatase activity; this appears to be caused by the reversible nature of the inhibition, coupled with induction/stabilization of the aromatase enzyme. To assess in situ effects within the breast, postmenopausal women with large primary breast cancers have been treated neoadjuvantly with aromatase inhibitors using a protocol that included (i) breast biopsy before treatment, (ii) definitive surgery after 3 months of treatment and (iii) infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before biopsy and surgery. With this study design, it has been shown that drugs such as letrozole profoundly inhibit in situ aromatase activity and reduce endogenous oestrogens within the breast.

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F Labrie

Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women’s health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women’s health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.

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R L Sutherland, C K W Watts and E A Musgrove

INTRODUCTION

The sex steroid hormones oestrogen and progesterone, in association with peptide hormones and growth factors, play a central role in normal mammary gland development including the control of differentiated function. There is also compelling evidence that oestrogen is intimately involved in the pathogenesis of breast cancer (Henderson et al. 1988). The majority of breast carcinomas retain some degree of steroid responsiveness and this has been exploited therapeutically by the use of agents which interfere with the production or action of oestrogenic steroids e.g. aromatase inhibitors, LH-RH agonists, and antioestrogens (Santen et al. 1990). Tamoxifen, a synthetic nonsteroidal antioestrogen, is currently the preferred treatment for hormoneresponsive breast cancer. Endocrine therapy, including tamoxifen treatment, induces objective responses in about one third of unselected patients and in almost 50% of oestrogen-receptor-positive (ER+) patients with advanced disease (Santen et al. 1990). More importantly a recent overview demonstrates significant reductions in risk of recurrence,

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R L Sutherland, O W J Prall, K M Alle, N R C Wilcken, R Hui, J R Ball, B Sarcevic, S M Henshall, E A Musgrove and C K W Watts

Introduction

The clinical studies of Beatson reporting responses to oophorectomy in women with advanced breast cancer (Beatson 1896) provided the first experimental evidence that an ovarian factor was critical for continued tumour growth in a proportion of breast cancers. It took another 58 years for this factor to be identified as oestrogen (Pearson et al. 1954). Subsequent research employing experimental models of carcinogen-induced mammary carcinoma revealed that oestrogen was essential for both the initiation and progression of breast cancer (Henderson et al. 1988). Studies with human breast cancer cell lines xenografted to athymic nude mice have demonstrated an absolute requirement for oestrogen in tumour formation and growth (Soule & McGrath 1980). Such observations provided the rationale for the introduction of antioestrogen therapy, the current treatment of choice for hormone-responsive breast cancer (Jordan & Murphy 1991). The subsequent demonstration of the efficacy of the antioestrogen tamoxifen in decreasing both

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Giorgio Secreto, Alessandro Girombelli and Vittorio Krogh

The aim of this review is to highlight the pivotal role of androgen excess in the development of breast cancer. Available evidence suggests that testosterone controls breast epithelial growth through a balanced interaction between its two active metabolites: cell proliferation is promoted by estradiol while it is inhibited by dihydrotestosterone. A chronic overproduction of testosterone (e.g. ovarian stromal hyperplasia) results in an increased estrogen production and cell proliferation that are no longer counterbalanced by dihydrotestosterone. This shift in the androgen/estrogen balance partakes in the genesis of ER-positive tumors. The mammary gland is a modified apocrine gland, a fact rarely considered in breast cancerogenesis. When stimulated by androgens, apocrine cells synthesize Epidermal Growth Factor (EGF) and EGF-related peptides that trigger the ErbB family receptors. These include the EGF receptor and the Human Epithelial Growth Factor 2, both well known for stimulating cellular proliferation. As a result, an excessive production of androgens is capable of directly stimulating growth in apocrine and apocrine-like tumors, a subset of ER-negative/AR-positive tumors. The key role of androgen excess in the genesis of different subtypes of breast cancer has significant clinical implications for both treatment and prevention. Our belief stems from a thorough analysis of the literature, where an abundance of evidence is present to justify a clinical trial that would investigate the effectiveness of treating the underlying excessive androgen production.

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R Kaaks, S Rinaldi, T J Key, F Berrino, P H M Peeters, C Biessy, L Dossus, A Lukanova, S Bingham, K-T Khaw, N E Allen, H B Bueno-de-Mesquita, C H van Gils, D Grobbee, H Boeing, P H Lahmann, G Nagel, J Chang-Claude, F Clavel-Chapelon, A Fournier, A Thiébaut, C A González, J R Quirós, M-J Tormo, E Ardanaz, P Amiano, V Krogh, D Palli, S Panico, R Tumino, P Vineis, A Trichopoulou, V Kalapothaki, D Trichopoulos, P Ferrari, T Norat, R Saracci and E Riboli

Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids — notably androgens and oestrogens — promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has been advocated for the prevention of osteoporosis and improved sexual well-being. We have conducted a case–control study nested within the European Prospective Investigation into Cancer and Nutrition. Levels of DHEA sulphate (DHEAS), (Δ4-androstenedione), testosterone, oestrone, oestradiol and sex-hormone binding globulin (SHBG) were measured in prediagnostic serum samples of 677 postmenopausal women who subsequently developed breast cancer and 1309 matched control subjects. Levels of free testosterone and free oestradiol were calculated from absolute concentrations of testosterone, oestradiol and SHBG. Logistic regression models were used to estimate relative risks of breast cancer by quintiles of hormone concentrations. For all sex steroids –the androgens as well as the oestrogens – elevated serum levels were positively associated with breast cancer risk, while SHBG levels were inversely related to risk. For the androgens, relative risk estimates (95% confidence intervals) between the top and bottom quintiles of the exposure distribution were: DHEAS 1.69 (1.23–2.33), androstenedione 1.94 (1.40–2.69), testosterone 1.85 (1.33–2.57) and free testosterone 2.50 (1.76–3.55). For the oestrogens, relative risk estimates were: oestrone 2.07 (1.42–3.02), oestradiol 2.28 (1.61–3.23) and free oestradiol (odds ratios 2.13 (1.52–2.98)). Adjustments for body mass index or other potential confounding factors did not substantially alter any of these relative risk estimates. Our results have shown that, among postmenopausal women, not only elevated serum oestrogens but also serum androgens are associated with increased breast cancer risk. Since DHEAS and androstenedione are largely of adrenal origin in postmenopausal women, our results indicated that elevated adrenal androgen synthesis is a risk factor for breast cancer. The results from this study caution against the use of DHEA(S), or other androgens, for postmenopausal androgen replacement therapy.

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D K Wyld, J D Chester and T J Perren

Introduction

Endocrine therapy has now been used as an effective treatment for breast cancer for 100 years. It was the first successful systemic treatment for cancer, initially becoming accepted following George Beatson's (1896) observations that, in a proportion of pre-menopausal women with advanced breast cancer, bilateral oophorectomy resulted in disease regression. Over the subsequent 75 years, several other endocrine therapies for breast cancer were developed, including other surgical approaches to hormone ablation therapy such as adrenalectomy (Huggins & Dao 1953) and hypophysectomy (Luft & Olivecrona 1953), and hormonal additive therapies, such as the use of pharmacological doses of androgens, oestrogens, progestogens and glucocorticoids. However, as none of these approaches led to a significant improvement in the rates of tumour regression, clinicians' enthusiasm in the 1960s and early 1970s became focused on the use of newly developing cytotoxic chemotherapy regimens. Then, in the 1970s, tamoxifen, and subsequently a range of other new endocrine agents, became available which were of low toxicity and generally well tolerated - high-dose oestrogens were quickly replaced by tamoxifen, and adrenalectomy by aromatase inhibitors. Measurement of hormone receptor levels also became available, allowing better selection of patients whose tumours might be hormonally responsive. In addition, some of the limitations of cytotoxic drugs in breast cancer were starting to become apparent.

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Ian S Fentiman

Male breast cancer (MBC) is a rare disease but, as a result of epidemiological collaborations, there is now greater clarity concerning endocrine risk factors. The significant rise in global age-standardised mean BMI in men is likely to lead to increases in incidence of maturity-onset diabetes and MBC. The metabolic changes accompanying obesity decrease androgens and sex hormone-binding globulin (SHBG), thereby increasing available oestrogens. The higher rates of MBC in North and Equatorial Africa are largely due to liver damage from endemic bilharziasis and hepatitis B causing elevated oestradiol (E2) levels from hepatic conversion of androgen. Klinefelter’s syndrome (XXY) is associated with a 50-fold increase in incidence of MBC compared with XY males, and this is the most pronounced evidence for testicular malfunction amplifying risk. Delay in presentation means that up to 40% of cases have stage III or stage IV disease at diagnosis. No randomised controlled trials have been reported on endocrine treatment of advanced disease or adjuvant/neoadjuvant therapy following or preceding surgery. Tamoxifen is the most effective endocrine therapy, but side effects can lead to non-compliance in a substantial number of men. Aromatase inhibitors are less effective because they do not inhibit testicular oestrogen production. There is an urgent need for collaborative trials to provide an evidence base for the most effective endocrine and least toxic therapies for men with breast cancer.

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S I Helle and P E Lønning

INTRODUCTION

While endocrine therapy has a well-defined role in the treatment of only three forms of cancer, its importance is illustrated by the fact that two of these diseases, carcinoma of the breast and carcinoma of the prostate, are among the most frequent cancers and are leading causes of cancer death in industrialised countries. Taking breast cancer into consideration, endocrine therapy with antioestrogens or oestrogen suppression (by gonadectomy in premenopausal women or use of aromatase inhibitors in postmenopausal women) has been found to cause tumour regression in advanced disease, and also to improve relapse-free and overall survival when used in the adjuvant setting. In prostatic carcinoma, androgen ablation or use of antiandrogens may cause tumour remission in the majority of patients treated for advanced disease.

There are several reasons to focus on different biochemical effects and alternative mechanisms of action in relation to endocrine therapy. Currently, we have a limited