Publication of the International Union Against Cancer

Because of large intra-individual variation in hormone levels, few studies have investigated the relation of serum sex hormones to breast cancer (BC) in premenopausal women. We prospectively studied this relation, adjusting for timing of blood sampling within menstrual cycle. Premenopausal women (5,963), recruited to the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort study, provided a blood sample in the 20 -24th day of their menstrual cycle. The hypothesis that breast cancer (BC) is related to ovarian function dates back over a century. 1 Epidemiological, in vitro and in vivo studies conducted in the second half of the last century made it clear that steroid sex hormones regulate cell proliferation and play a major role in promoting BC. 2,3 Several mechanistic hypotheses for the development of BC have been proposed, 2,4 but until recently, hormone measurements by epidemiological studies have failed to corroborate any of them. Over the last decade, however, several prospective cohort studies in postmenopausal women have shown that BC development is preceded by alterations in levels of circulating sex hormones. 5 High serum levels of free and total estradiol, total testosterone and other estrogens and androgens, as well as low serum levels of sex hormone-binding globulin (SHBG), have been found to be implicated in the risk of BC. 5 Our own study also indicated that high serum levels of free testosterone are associated with the risk of BC. 6 These prospective investigations were carried out with the help of thousands of healthy women who provided blood samples for storage and future nested-in-the-cohort case-control analyses. Compared to case control studies in clinical settings, the strengths of prospective studies are that control subjects belong to the same cohort that generates the incident disease cases and that blood is collected before the diagnosis of cancer thereby excluding abnormal values that may be due to overt illness. Hormone measurements in premenopausal women are difficult to interpret because serum levels change with the menstrual cycle and because cycle length varies inter-and intra-individually. Only a few prospective investigations have addressed the role of sex hormone levels in BC before the menopause; 7-10 all considered small numbers of case women and did not produce clear results. The endocrine basis of BC in premenopause is therefore the subject of several disparate hypotheses. These include the hypothesis of Grattarola, advanced in the 1960s, 11-12 that hyperandrogenism with luteal inadequacy plays a role in the induction of BC, and of Henderson et al. The present prospective study was designed to investigate whether luteal inadequacy and hyperandrogenism increase the risk of BC in premenopausal women. We collected blood samples from premenopausal women participating in the study on Hormones and Diet in the Etiology of Breast Tumors (ORDET). 6,14 Samples were taken between the 20th and 24th day of the cycle (theoretically during the mid luteal phase). The first day of menstrual bleeding subsequent to sampling was also recorded to provide an additional data point for correctly locating the sampling day within the cycle. In these women, we analyzed the relationship between BC and serum levels of the androgens dehydroepiandrosterone sulfate (DHEAS), total testosterone, free testosterone, androstenedione and androstanediol-glucoronide (Adiol-G), and also progesterone, 17-OH-progesterone, SHBG, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Estradiol was not considered in the present analysis because of its extraordinary intra-individual variation in premenopausal women

Androgen receptors and serum testosterone levels identify different subsets of postmenopausal breast cancers

<p>Abstract</p> <p>Background</p> <p>Androgen receptors (AR) are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development.</p> <p>Methods</p> <p>AR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0%) and AR-poorly (1%-30%), AR-moderately (>30%-60%), and AR-highly (>60%) positive.</p> <p>Results</p> <p>Statistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER)- and progesterone receptor (PR)-positive status (<it>P</it> trend<0.001). Mean testosterone levels were significantly higher in the AR-high category than in the other categories combined (<it>P</it>=0.022), although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16), but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82). In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73–5.02): the association was present in both age groups (<65 and ≥65 years). In the ER-negative group, elevated testosterone levels were found associated (borderline significance) with AR-absent expression (OR 2.82, 95% CI, 0.98-8.06). In this ER-negative/AR-absent subset of tumors, elevated testosterone levels cannot stimulate cancer growth either directly or after conversion into estrogens, but they probably induce increased synthesis of some other substance that is responsible for cancer growth through binding to its specific receptor.</p> <p>Conclusions</p> <p>The findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.</p