In situ estrogen production and its regulation in human breast carcinoma: From endocrinology to intracrinology

Abstract

The great majority of breast carcinomas arising in postmenopausal women are estrogen dependent or positive for estrogen receptor (ER) in carcinoma cells despite markedly low plasma or circulating estrogen concentrations. In these patients, biologically active estrogens are locally produced from circulating inactive steroids including adrenal androgens in an intracrine mechanism in the breast cancer tissues and confer estrogenic activities on carcinoma cells. A series of enzymes are involved in this intra-tumoral or in situ production of estrogens in breast carcinoma tissues but aromatase, a member of the cytochrome P450 family, is a key enzyme of estrogen production through conversion from circulating adrenal androgens in estrogen-dependent postmenopausal breast cancer. It then becomes important to identify the sites of this estrogen production. There has been, however, controversy regarding intra-tumoral localization of aromatase in breast carcinoma, especially whether intra-tumoral production of estrogens through aromatase occurs in carcinoma or stromal cells. The enzyme was demonstrated to be expressed in both carcinoma and stromal cells in breast carcinoma tissues on immunohistochemistry with a well-characterized mAb 677 and combined laser capture microdissection/qualitative reverse transcriptase-polymerase chain reaction. Intra-tumoral aromatase in both of these cell types was subsequently demonstrated to be induced by carcinoma-stromal interactions associated with carcinoma invasion in breast tissue. The signals through various nuclear receptors, especially estrogen-related receptor-a in carcinoma cells and liver receptor homologue-1 in adipocytes adjacent to carcinoma invasion, in conjunction with various cytokines and/or growth factors, play pivotal roles in this induction of intratumoral aromatase. This increased aromatase subsequently results in increased in situ estrogen concentrations of breast cancer. Aromatase inhibitors are currently established as the gold standard for the treatment for ER-positive breast carcinoma but resistance to the therapy still remains to be solved by other modes of suppression of intra-tumoral estrogen production.

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

“…These results suggest that a serous E1 concentration is sustained at a relatively higher level in postmenopausal women by aromatase distributing systemically, and that E1 concentration in postmenopausal cancerous tissue is mostly dependent on diffusion from the serum. This is an unexpected result, because aromatase has been reported to be abundant in postmenopausal breast cancerous tissue (3)(4)(5)(6)(7) and has been expected to effectively convert serous Adione into E1, finally leading to the elevation of E2 concentration in tumor tissue (Fig. 1).…”

“…(3) Increased aromatase expression in postmenopausal breast cancer tissue has been reported by many authors; (3)(4)(5)(6)(7) however, the activity of aromatase, which plays a rate-limiting step in estrogen biosynthesis, might not be enough to keep up with HSD-1 activity.…”

“…17b-Hydroxysteroid deydrogenase (HSD)-1 converts estrone (E1) into estradiol (E2), the most potent estrogen. In breast cancer tissue, aromatase, (3)(4)(5)(6)(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.…”

“…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).…”

“…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.…”