Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene‐3β, 17β‐diol

Abstract

Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen-metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3b, 17b-diol (Aenediol) or 5a-androstane-3b, 17b-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5a-Androstane-3b, 17b-diol was undetectable in most samples. Androstene-3b, 17b-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated. (Cancer Sci 2011; 102: 1848-1854 E strogen plays an important role in the pathobiology of breast cancer.(1,2) In postmenopausal women, in whom ovarian function has decreased, the peripheral metabolism of estrogens via estrogen-metabolizing enzymes is important (Fig. 1). (3,4) Peripheral aromatase converts circulating androgens, such as dehydroepiandrosterone (DHEA) and androstenedione (Adione), from the adrenal gland or ovary into estrogens. Steroid sulfatase (STS) hydrolyzes biologically-inactive sulfates of sex steroids, both estrogens and androgens, producing active steroids. 17b-Hydroxysteroid deydrogenase (HSD)-1 converts estrone (E1) into estradiol (E2), the most potent estrogen. In breast cancer tissue, aromatase, (3-7) STS, (8)(9)(10) and HSD-1 (11) have been reported to be abundant. An increase of E2 concentration in cancerous tissue, compared with the serum in postmenopausal women, has been explained by those enzymes localized in the tumor tissue.(4) Estrone sulfotransferase and HSD-2 play opposite roles to STS and HSD-1, respectively (Fig. 1). Aromatase inhibitors (AI) have been standardized for the treatment of postmenopausal patients with hormone receptor-positive breast cancers, (12) in the expectation of decreasing estrogens. Inhibitors of STS (13) or HSD-1 (14,15) have been also devel...

Estrogen-Related Factors in the Frontal Lobe of Alzheimer’s Disease Patients and Importance of Body Mass Index

“…The concentrations of E1 and Adione in the frontal lobe observed in the present study were several times higher, while that for E2 was several score times higher, than those in the postmenopausal serum reported in other studies 31 . The higher concentration of E1 and Adione in the frontal tissue than the serum can be mostly ascribed to their lipophilia, but this is unlikely for E2′s remarkably higher concentration.…”

Estrogen and cancers of the colorectum, breast, and lung in postmenopausal women

“…This observation suggests the importance of systemic (not tumor localized) aromatase and tumor localized HSD‐1 (Fig. b) . Lønning et al .…”

“…On the contrary, HSD‐1 levels were higher in HR‐positive than in HR‐negative carcinomas, whereas HSD‐2 exhibited the opposite results . This is in line with the elevation of E2, but not E1, in HR‐positive postmenopausal tumors described above …”

Complexities of androgen receptor signalling in breast cancer

“…3b-diol has been shown to bind ERa and stimulate proliferation in ERa-positive T-47D and ZR-75-1 breast cancer cell lines , demonstrating that these androgen metabolites can have weak oestrogenic properties, thus enhancing ERa function while decreasing AR activity through metabolism of DHT. In breast cancer tissues, presence of the most potent oestrogen, E 2 , may minimise the biological relevance of these weakly oestrogenic metabolites to breast cancer biology (Honma et al 2011). However, in an oestrogen-deplete environment, such as in postmenopausal women or women undergoing aromatase inhibitor therapy, 3a-diol and 3b-diol may exert a proliferative effect on breast epithelial cells.…”