scholarly journals Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals

2012 ◽  
Vol 302 (8) ◽  
pp. E1009-E1015 ◽  
Author(s):  
Laura L. Hernandez ◽  
Karen A. Gregerson ◽  
Nelson D. Horseman
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Related Protein ◽  
Bone Demineralization ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Expression

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.

scholarly journals Parathyroid Hormone-related Protein Regulates Tumor-relevant Genes in Breast Cancer Cells

2006 ◽  
Vol 281 (21) ◽  
pp. 14563-14572 ◽  
Author(s):  
Angela Dittmer ◽  
Martina Vetter ◽  
Dario Schunke ◽  
Paul N. Span ◽  
Fred Sweep ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parathyroid Hormone ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein

Mid-region parathyroid hormone-related protein (PTHrP) binds chromatin of MDA-MB231 breast cancer cells and isolated oligonucleotides “in vitro”

2006 ◽  
Vol 105 (1) ◽  
pp. 105-116 ◽  
Author(s):  
Rosalia Sirchia ◽  
Marcella Priulla ◽  
Giulia Sciandrello ◽  
Fabio Caradonna ◽  
Giuseppa Barbata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parathyroid Hormone ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein

scholarly journals Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

2003 ◽  
Vol 372 (3) ◽  
pp. 787-797 ◽  
Author(s):  
Ralph K. LINDEMANN ◽  
Melanie BRAIG ◽  
Craig A. HAUSER ◽  
Alfred NORDHEIM ◽  
Jürgen DITTMER
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Expression ◽  
Mcf 7

Parathyroid hormone-related protein (PTHrP) promotes the metastatic potential and proliferation of breast cancer cells, and acts anti-apoptotically. In invasive MDA-MB-231 breast cancer cells, transforming growth factor β-regulated PTHrP synthesis is mediated by an Ets1/Smad3-dependent activation of the PTHrP P3 promoter. In the present study, we studied the regulation of PTHrP expression in non-invasive, Ets1-deficient and transforming growth factor β-resistant MCF-7 cells. We found PMA to be a strong stimulator of P3-dependent PTHrP expression in MCF-7 cells. Mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase 1 (MEK-1)/ERK1/2 inhibitor PD98059 interfered with this activity. Promoter studies revealed that the PMA effect depended on the Ets and stimulating protein-1 (Sp1)-binding sites. Of several Ets factors tested, Ets2, but not Ese-1, Elf-1 or Ets1, supported the PMA-dependent increase in promoter activity. PD98059 and a threonine to alanine mutation of the ERK1/2-responsive Ets2 phosphorylation site at position 72 inhibited the Ets2/PMA effect. Activated protein kinase C (PKC)ε could mimic PMA by stimulating the P3 promoter alone or in co-operation with Ets2 in an MEK-1/ERK1/2-dependent manner. Activated PKCα, although capable of co-operating with Ets2, failed to induce transcription from the P3 promoter on its own. The Ets2/PKCα synergistic effect was neither sensitive to PD98059 nor to Thr72/Ala72 mutation. PMA neither increased the expression of Sp1 nor modulated the transcriptional activity of Sp1. However, it induced the displacement of a yet unknown factor from the Sp1-binding site, which may result in Sp1 recruitment to the promoter. Our results suggest an ERK1/2-dependent Ets2/PKCε synergism to be involved in PTHrP expression in MCF-7 breast cancer cells.

Cortisol, parathyroid hormone-related protein and the onset of calcium secretion by the mammary gland of the goat

1997 ◽  
Vol 64 (4) ◽  
pp. 633-636
Author(s):  
GORDON E. THOMPSON ◽  
S. KHAWAR ABBAS ◽  
CARL HOLT ◽  
ANTHONY D. CARE
Keyword(s):  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Tight Junctions ◽  
Calcium Transport ◽  
Extracellular Fluid ◽  
Secretory Cells ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Calcium Secretion

During lactogenesis in the goat, the onset of secretion of calcium into milk occurs at parturition (Thompson et al. 1995) at approximately the same time as the onset of secretion of parathyroid hormone-related protein (PTHrP) by the mammary gland (Ratcliffe et al. 1992); these events may be unrelated or PTHrP may be involved in calcium transport from blood to milk.Parturition in goats is initiated by fetal secretion of cortisol (Flint et al. 1978) and maternal secretion of cortisol also increases (Paterson & Linzell, 1971). Injecting cortisol locally into the sinus of a mammary gland of the late-pregnant goat when the tight junctions between secretory epithelial cells appear to be ‘loose’, and injectate can reach the basolateral surfaces of secretory cells, stimulates an early tightening of these junctions (Thompson, 1996) as occurs naturally at parturition. This tightening can be produced by an increased concentration of ionized calcium in the extracellular fluid of the gland (Neville & Peaker, 1981).The experiments reported here were undertaken to determine if cortisol injection stimulates the mammary gland to secrete both PTHrP and calcium before parturition.

Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development

Development ◽  
1998 ◽  
Vol 125 (7) ◽  
pp. 1285-1294 ◽  
Author(s):  
J.J. Wysolmerski ◽  
W.M. Philbrick ◽  
M.E. Dunbar ◽  
B. Lanske ◽  
H. Kronenberg ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Related Protein ◽  
Transgenic Expression ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Receptor

Parathyroid hormone-related protein (PTHrP) was originally discovered as a tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in normal tissues and growing evidence suggests that it is an important developmental regulatory molecule. We had previously reported that overexpression of PTHrP in the mammary glands of transgenic mice impaired branching morphogenesis during sexual maturity and early pregnancy. We now demonstrate that PTHrP plays a critical role in the epithelial-mesenchymal communications that guide the initial round of branching morphogenesis that occurs during the embryonic development of the mammary gland. We have rescued the PTHrP-knockout mice from neonatal death by transgenic expression of PTHrP targeted to chondrocytes. These rescued mice are devoid of mammary epithelial ducts. We show that disruption of the PTHrP gene leads to a failure of the initial round of branching growth that is responsible for transforming the mammary bud into the rudimentary mammary duct system. In the absence of PTHrP, the mammary epithelial cells degenerate and disappear. The ability of PTHrP to support embryonic mammary development is a function of amino-terminal PTHrP, acting via the PTH/PTHrP receptor, for ablation of the PTH/PTHrP receptor gene recapitulates the phenotype of PTHrP gene ablation. We have localized PTHrP expression to the embryonic mammary epithelial cells and PTH/PTHrP receptor expression to the mammary mesenchyme using in situ hybridization histochemistry. Finally, we have rescued mammary gland development in PTHrP-null animals by transgenic expression of PTHrP in embryonic mammary epithelial cells. We conclude that PTHrP is a critical epithelial signal received by the mammary mesenchyme and involved in supporting the initiation of branching morphogenesis.

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