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Estrogens and Antiestrogens Stimulate Release of Bone Resorbing Activity by Cultured Human Breast Cancer Cells

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Estrogens and Antiestrogens Stimulate Release of Bone Resorbing Activity by Cultured Human Breast Cancer Cells Estrogens and antiestrogens stimulate release of bone resorbing activity by cultured human breast cancer cells. A Valentin-Opran, … , S Saez, G R Mundy J Clin Invest. 1985;75(2):726-731. https://doi.org/10.1172/JCI111753. Research Article Patients with advanced breast cancer may develop acute, severe hypercalcemia when treated with estrogens or antiestrogens. In this study, we examined the effects of estrogens and related compounds on the release of bone resorbing activity by cultured human breast cancer cells in vitro. We found that the estrogen receptor positive breast cancer cell line MCF-7 releases bone resorbing activity in response to low concentrations of 17 beta-estradiol. Bone resorbing activity was also released in response to the antiestrogen nafoxidine. Other steroidal compounds had no effect on the release of bone resorbing activity. Estrogen-stimulated release of bone resorbing activity occurred with live bone cultures, but not with devitalized bones, indicating that the effect was bone cell mediated. The breast cancer cell line MDA-231, which does not have estrogen receptors, did not release bone resorbing activity in response to 17 beta- estradiol or nafoxidine. Release of the bone resorbing activity by MCF-7 cells incubated with 17 beta-estradiol was inhibited by indomethacin (10 microM) and flufenamic acid (50 microM), two structurally unrelated compounds that inhibit prostaglandin synthesis. Concentrations of 17 beta-estradiol and nafoxidine that caused increased release of bone resorbing activity by the breast cancer cells caused a four- to fivefold increase in release of prostaglandins of the E series by MCF-7 cells. These data may explain why some patients with advanced breast cancer […] Find the latest version: https://jci.me/111753/pdf Estrogens and Antiestrogens Stimulate Release of Bone Resorbing Activity by Cultured Human Breast Cancer Cells Alexandre Valentin-Opran, Gabriel Eilon, Simone Saez, and Gregory R. Mundy Laboratoire de Biologie Medicale Centre L. Berard, 69008 Lyon, France; Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06032; and Department of Medicine/Endocrinology, University of Texas Health Science Center at San Antonio, Texas 78284 Abstract To develop more effective forms of therapy for breast cancer that has metastasized to bone, we need to understand Patients with advanced breast cancer may develop acute, severe the mechanisms by which breast cancer cells influence bone hypercalcemia when treated with estrogens or antiestrogens. cell metabolism. The most important abnormality appears to In this study, we examined the effects of estrogens and related be an increase in bone resorption with resultant lytic metastases compounds on the release of bone resorbing activity by cultured and often hypercalcemia (1). The mechanism by which bone human breast cancer cells in vitro. We found that the estrogen resorption is increased in breast cancer is unknown, although receptor positive breast cancer cell line MCF-7 releases bone a number of studies have implicated prostaglandins (6-9), resorbing activity in response to low concentrations of 17,B- which increase the activity of osteoclasts, the major bone estradiol. Bone resorbing activity was also released in response resorbing cells. It has also been shown that breast cancer cells to the antiestrogen nafoxidine. Other steroidal compounds had can directly resorb bone in vitro by the production of hydrolytic no effect on the release of bone resorbing activity. Estrogen- enzymes (10, 11). stimulated release of bone resorbing activity occurred with live Steroid hormones clearly influence breast cancer cell growth. bone cultures, but hot with devitalized bones, indicating that Many tumors have steroid hormone receptors (12, 13), and the effect was bone cell mediated. The breast cancer cell line some tumors will respond to hormonal manipulations, includ- MDA-231, which does not have estrogen receptors, did not ing the administration of estrogens, antiestrogens, or androgens release bone resorbing activity in respojise to 17,6-estradiol or (14). It has been known for 40 yr that administration of nafoxidine. Release of the bone resorbing activity by MCF-7 estrogens or antiestrogens may lead to the precipitation of cells incubated with 17,B-estradiol was inhibited by indomethacin acute and severe hypercalcemia (15-18), even when tumor (10 tiM) and flufenamic acid (50 ,uM, two structurally unrelated growth regresses in response to the hormone (18, 19). 15% of compounds that inhibit prostaglandin synthesis. Concentrations estrogen receptor positive women treated with estrogens develop of 17,B-estradiol and nafoxidine that caused increased release acute severe hypercalcemia (16), and -2% of women with of bone resorbing activity by the breast cancer cells caused a advanced breast cancer develop acute hypercalcemia when four- to fivefold increase in release of prostaglandins of the E treated with antiestrogens such as nafoxidine or tamoxifen series by MCF-7 cells. These data may explain why some (20). The mechanism of hormone-stimulated hypercalcemia patients with advanced breast cancer develop acute hypercal- in breast cancer is unknown. cemia when treated with estrogens or antiestrogens, and why In this study, we examined the effects of estrogens and bone metastases are more common in patients with estrogen antiestrogens on the production of bone resorbing activity by receptor positive tumors. cultured human breast cancer cell lines in vitro. We found that 17f3-estradiol and nafoxidine caused increased release of bone resorbing activity by cultured human breast cancer cells Introduction with estrogen receptors. This effect was inhibited by drugs that block prostaglandin synthesis. The production of bone resorbing Breast cancer, the most common malignancy in women, by the breast cancer cells corresponded to their increased skeleton Metastatic bone lesions activity frequently involves the (1). release of prostaglandins of the E series. may be osteolytic or osteosclerotic. They frequently lead to intractable pain, fractures, and occasionally hypercalcemia. Methods Approximately 90% of women dying with breast cancer have bone metastases (2-4), and >30% develop hypercalcemia (5). The experiments described in this report were performed in two Once tumor cells involve bone, only palliative treatment with separate laboratories, one in Farmington, Connecticut, the other in hormonal therapy (such as estrogens, antiestrogens, or andro- Lyon, France. In one laboratory (Farmington, Connecticut), bone resorbing activity was assessed using conditioned media harvested from gens) or chemotherapy is possible. cultured MCF-7 cells incubated with fetal rat long bones in organ culture. In the other laboratory (Lyon, France) bone resorbing activity from MCF-7 cells was assessed by co-culture of MCF-7 cells with Address reprint requests to Dr. Mundy. neonatal mouse calvaria in organ culture. Receivedfor publication 13 December 1983 and in revisedform 20 September 1984. Bone resorbing assays Fetal rat long bone assays. These assays were performed in Connecticut. J. Clin. Invest. The method for assessing bone resorbing activity has been described ©) The American Society for Clinical Investigation, Inc. in detail previously (21, 22). Bones were obtained from the fetuses of 0021-9738/85/02/0726/06 $ 1.00 pregnant rats on the 19th d of gestation. On the 18th d the rats were Volume 75, February 1985, 726-731 given a subcutaneous injection of 0.05 mCi of 45Ca. The radius and 726 A. Valentin-Opran. G. Eilon, S. Saez, and G. R. Mundy ulna were explanted from the fetus and placed in organ culture for 72 anapolis, IN) and the IgG sorb technique. This assay has 20% cross- h. The first 24-h period was a preculture period to allow for exchange reactivity with prostaglandin El. Prostaglandins were assayed in the of loosely complexed 45Ca with stable calcium in the control media. cell culture supernatants 6 h after exposure of the tumor cells to the Conditioned media harvested from MCF-7 or MDA-23 1 cultured steroid compounds. After addition of 3H-PGE2 (New England Nuclear, human breast cancer cells were incubated with the bones over the Boston, MA) for calculation of recovery, the culture supernates were following 48-h period. extracted twice with 2:1 ethylacetate/cyclohexane, and the extracts Both of these tumor cell lines were derived originally from malignant were dried under nitrogen and then reconstituted with 0.2 M phosphate pleural effusions from two different patients with disseminated breast buffer (pH 7.9) containing 1% rabbit serum. Using this method, -70% cancer (23, 24). Our cells were obtained from E.G. and G. Mason of the PGE2 is recoverable. Research Institute, Rockville, MD. Cell culture media used in these experiments was harvested from cultures that were near confluency. Cell protein The MCF-7 cells were cultured in Dulbecco's modified Eagle's medium The total protein content of cultured tumor cells per well was measured (Gibco Laboratories, Grand Island, NY) with 10% fetal calf serum in cell sonicates using the technique of Lowry et al. (26). (Gibco). The MDA-231 cells were grown in LI 5 medium (Gibco) with similar amounts of fetal calf serum. The fetal calf serum was stripped Cell DNA content by exposure to charcoal to remove steroid hormones. The cells were DNA content of the cultured tumor cells was determined using the grown to confluency and cultures routinely split every week. In some ethidium bromide technique of Karsten
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