Effects of secretory products of breast cancer cells on osteoblast-like cells.
The pathogenesis of breast cancer-induced osteolysis remains largely unknown. To evaluate the potential role of osteoblasts as target cells during this process, we incubated SaOS-2 human osteoblast-like cells (OBL) with culture media conditioned by proliferative (PM, 'Proliferation Media') or confluent (CfM, 'Confluence Media') MCF-7 human breast cancer cells. CfM decreased the growth of OBL by 26% (P < 0.01) while PM was without significant effect on this parameter. In contrast, both PM and CfM obtained from MCF-7 cultures increased the cyclic AMP (cAMP) response of OBL to the osteolytic agents PTH (10(-8) M) and PTH-related peptide (PTHrP, 10(-8) M) by a factor of about 3 (P < 0.001), and to prostaglandin E(2) (PGE(2),10(-6) M) by a factor of about 2 (P < 0.01). No significant modulation of OBL growth or sensitivity to PTH, PTHrP, or PGE2 was induced by media obtained from HBL-100 non-malignant immortalized breast epithelial cell cultures. 17betaestradiol (E(2), 10(-8) M) and the antiestrogen tamoxifen (Tam, 10(-7) M) added for 48 h to MCF-7 cultures before collecting conditioned media attenuated and potentiated, respectively, the PM- but not the CfM-induced increase in the response of OBL to PTH or PTHrP Along the same line, the addition to MCF-7 conditioned media of a polyclonal anti-transforming growth factor-beta (TGF-beta) antibody attenuated by about 25% (P < 0.01) the PM-induced increase in OBL response to PTH and PTHrP while abrogating the modulatory effects of E(2) and Tam on that response. Together, our results indicate that MCF-7 breast cancer cells secrete factors which inhibit the growth of OBL and increase their sensitivity to various osteolytic agents. TGF-beta was only partly responsible for these effects, and accounts for their modulation by E(2) and Tam. The identification of other osteoblast-modulatory factor(s) should contribute to a better understanding and treatment of breast cancer-induced osteolysis.
Lacroix
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Bone Metabolism Unit, Service de Medecine et Laboratoire d'Investigation Clinique H.J. Tagnon, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium.
Siwek
B
B
Body
J J
JJ
D000230:Adenocarcinoma / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects*; D010014:Osteolysis / Q000209:etiology; D010281:Parathyroid Hormone / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000378:metabolism
D017077:Culture Media, Conditioned; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D016212:Transforming Growth Factor beta; D005576:Colforsin; D000242:Cyclic AMP; D015232:Dinoprostone