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Identification of Steroid Sulfate Transport Processes in the Human Mammary Gland

Division of Clinical Pharmacology and Toxicology (F.P., R.D.H., P.J.M., M.V.S.-P.), Department of Internal Medicine, and Department of Pathology (Z.V.), University Hospital of Zürich; and Institute of Pharmaceutical Chemistry (F.P., R.D.H., G.F.), Department of Applied Biosciences, Swiss Federal Institute of Technology, Zürich 8091, Switzerland

Address all correspondence and requests for reprints to: M. V. St-Pierre, Ph.D., Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zürich, 100 Rämistrasse, Zürich 8091, Switzerland. E-mail: stpierre{at}kpt.unizh.ch.

Circulating hormones and local biotransformation of steroid precursors are both sources of estrogen in human mammary tissue. Estrone-3-sulfate (E₁S) is an important estrogenic form in premenopausal women, and dehydroepiandrosterone sulfate (DHEAS) constitutes a major adrenal precursor. Membrane transport systems that govern delivery of these anionic steroid conjugates to the mammary gland were investigated. RNA was screened by RT-PCR and Northern blotting for expression of organic anion transporting polypeptide (OATP) (solute carrier family 21A) and organic anion transporter (OAT) (solute carrier family 22A) gene families. OATP-B (SLC21A9) was the major carrier expressed; OATP-D (SLC21A11) and OATP-E (SLC21A12) were less abundant. In normal sections, OATP-B immunolocalized to the myoepithelium that surrounds the ductal epithelial cells. In invasive carcinoma, ductal epithelial cells were positive. OATP-B was characterized in stable transfected Chinese hamster ovary cells. E₁S affinity constant (K_m) [K_m = 5 µmol/liter, maximum velocity (V_max) V_max = 777 pmol/mg·min] and DHEAS (K_m = 9 µmol/liter, V_max = 85 pmol/mg·min) were substrates. The prostaglandins (PG) A₁ and PGA₂ stimulated uptake of E₁S and DHEAS by increasing V_max 2-fold but not changing K_m. The effect of PGA was selectively blocked by the lipophilic thiol reagent N-ethylmaleimide but not by the hydrophilic acetamido-4'(iodoacetyl)aminostilbene-2,2'-disulfonic acid, suggesting an interaction between the electrophilic cyclopentenone ring and specific cysteine residues of OATP-B.

This work was supported by Grant 01B38 from the Novartis Foundation for Biomedical Research (to M.V.S.-P.), a grant from the University of Zürich Forschungskommission (to M.V.S.-P.), and grants from the National Science Foundation, Switzerland (31-67173.01, to M.V.S.-P.; and 31-64140.00, to P.J.M.).

Abbreviations: CHO, Chinese hamster ovary; DAPI, 4'-6-diamidino-2-phenylindole; DHEA, dehydroepiandrostenedione; DHEAS, dehydroepiandrosterone sulfate; E₁, estrone; E₁S, estrone 3-sulfate; E₂, 17ß-estradiol; IASD, acetamido-4'-(iodoacetyl)amino-stilbene-2,2'-disulfonic acid; K_m, affinity constant; NEM, N-ethylmaleimide; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; PG, prostaglandin(s); SSC, saline sodium citrate; V_max, maximum velocity.

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