Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals.
Breast cells drive bone demineralization during lactation and metastatic cancers. A shared mechanism among these physiological and pathological states is endocrine secretion of parathyroid hormone-related protein (PTHrP), which acts through osteoblasts to stimulate osteoclastic bone demineralization. The regulation of PTHrP has not been accounted for fully by any conventional mammotropic stimuli or tumor growth factors. Serotonin (5-HT) synthesis within breast epithelial cells is induced during lactation and in advancing breast cancer. Here we report that serotonin deficiency (knockout of tryptophan hydroxylase-1) results in a reduction of mammary PTHrP expression during lactation, which is rescued by restoring 5-HT synthesis. 5-HT induced PTHrP expression in lactogen-primed mammary epithelial cells from either mouse or cow. In human breast cancer cells 5-HT induced both PTHrP and the metastasis-associated transcription factor Runx2/Cbfa1. Based on receptor expression and pharmacological evidence, the 5-HT2 receptor type was implicated as being critical for induction of PTHrP and Runx2. These results connect 5-HT synthesis to the induction of bone-regulating factors in the normal mammary gland and in breast cancer cells.
Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio, USA.
Laura L
LL
Hernandez
Karen A
KA
Gregerson
Nelson D
ND
Horseman
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007774:Lactation / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
D050659:Core Binding Factor Alpha 1 Subunit; D009363:Neoplasm Proteins; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; C493709:RUNX2 protein, human; D044348:Receptors, Serotonin, 5-HT2; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase