Regulation of parathyroid hormone-related protein expression in MCF-7 breast carcinoma cells by estrogen and antiestrogens

Expression of parathyroid hormone-related protein (PTHrP) in breast carcinoma is a frequent cause of the paraneoplastic syndrome of hypercalcemia. In response to treatment with estrogen or tamoxifen, some breast cancer patients also develop a transient hypercalcemia. Therefore, the effect of 17β-estradiol (E₂), tamoxifen, or its more potent metabolite, 4-hydroxytamoxifen (OH-tamoxifen), on PTHrP expression in an estrogen receptor (ER)-positive breast carcinoma cell line (MCF-7) was evaluated. E₂ increased PTHrP mRNA levels in MCF-7 cells and stimulated PTHrP(1-86) release in a dose-dependent fashion (10^-10-10^-6 M). Tamoxifen and OH-tamoxifen also stimulated PTHrP release in a concentration-dependent fashion that paralleled their relative ER binding affinities (10^-6 or 10^-8-10^-6 M, respectively). Combined treatment with the partial estrogen agonist, OH-tamoxifen, and E₂ decreased E₂-stimulated PTHrP secretion in MCF-7 cells to the levels seen with OH-tamoxifen treatment alone. These results suggest that transient estrogen- or tamoxifen-induced hypercalcemia in patients with breast carcinoma may be a PTHrP-mediated effect that is a marker of ER positivity.