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.

scholarly journals All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor β to stimulate apoptosis in MCF-7 breast cancer cells

2004 ◽  
Vol 183 (2) ◽  
pp. 395-404 ◽  
Author(s):  
D N Danforth
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Protein Expression ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transforming Growth Factor ◽  
Synergistic Effects ◽  
Transforming Growth Factor Β ◽  
Mcf 7

The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throughout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis. The negative growth factor-transforming growth factor β (TGFβ) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGFβ1 secretion over 72 h. TGFβ1 alone had no apoptotic effects on these cells; however, TGFβ1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGFβ1+AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGFβ antibody did not block down-regulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGFβ, although TGFβ may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.

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 SGK3 Is an Estrogen-Inducible Kinase Promoting Estrogen-Mediated Survival of Breast Cancer Cells

2011 ◽  
Vol 25 (1) ◽  
pp. 72-82 ◽  
Author(s):  
Yuanzhong Wang ◽  
Dujin Zhou ◽  
Sheryl Phung ◽  
Selma Masri ◽  
David Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Cell Survival ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Dependent Manner ◽  
Binding Regions ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a protein kinase of the AGC family of protein kinase A, protein kinase G, and protein kinase C and functions downstream of phosphatidylinositol 3-kinase (PI3K). Recent study revealed that SGK3 plays a pivotal role in Akt/protein kinase B independent signaling downstream of oncogenic PI3KCA mutations in breast cancer. Here we report that SGK3 is an estrogen receptor (ER) transcriptional target and promotes estrogen-mediated cell survival of ER-positive breast cancer cells. Through a meta-analysis on 22 microarray studies of breast cancer in the Oncomine database, we found that the expression of SGK3 is significantly higher (5.7-fold, P < 0.001) in ER-positive tumors than in ER-negative tumors. In ER-positive breast cancer cells, SGK3 expression was found to be induced by 17β-estradiol (E2) in a dose- and time-dependent manner, and the induction of SGK3 mRNA by E2 is independent of newly synthesized proteins. We identified two ERα-binding regions at the sgk3 locus through chromatin immunoprecipitation with massively parallel DNA sequencing. Promoter analysis revealed that ERα stimulates the activity of sgk3 promoters by interaction with these two ERα-binding regions on E2 treatment. Loss-of-function analysis indicated that SGK3 is required for E2-mediated cell survival of MCF-7 breast carcinoma cells. Moreover, overexpression of SGK3 could partially protect MCF-7 cells against apoptosis caused by antiestrogen ICI 182,780. Together, our study defines the molecular mechanism of regulation of SGK3 by estrogen/ER and provides a new link between the PI3K pathway and ER signaling as well as a new estrogen-mediated cell survival mechanism mediated by SGK3 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
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