PTHrP inhibits BMP-6 expression through the PKA signaling pathway in breast cancer cells.
BACKGROUND
PTHrP, a mediator of humoral hypercalcemia of malignancy, is considered as a potential activator to induce breast cancer cells metastasizing to bone. However, recent clinical evidences and basal research results prove that PTHrP expression in primary tumors indicates good prognosis. BMP-6, as a member of TGF-β superfamily, is closely correlated with tumor differentiation and skeletal metastasis.


OBJECTIVE
These experiments were designed to investigate the molecular mechanism of PTHrP regulating BMP-6 in breast cancer cells.


RESULTS
Through detecting mRNA expression levels of PTHrP and BMP-6 in 35 breast cancer specimens, the two genes' expression were proved to be negatively correlated. Moreover, PTHrP (1-40), instead of PTHrP (107-139), inhibited BMP-6 mRNA expression in MCF-7 cells, indicating that PTHrP exerts its effect on BMP-6 through membranous PTHrP receptor. Inhibitors against signaling pathways downstream of PTHrP were utilized. H89, the PKA pathway inhibitor, eliminated the inhibitory effect of PTHrP on BMP-6. In addition, silencing of BMP-6 strengthened the antimitogenic effect of PTHrP.


CONCLUSIONS
These results suggest that PTHrP acts as the upstream molecule of BMP-6, and exerts antimitogenic effect via reducing BMP-6 mRNA expression through PKA signaling pathway in breast cancer cells.
Mi
Dong
D
Laboratory of Molecular Genetics, Medical College, Nankai University, Tianjin 300071, People's Republic of China.
Zhang
Ming
M
Yan
Ji-dong
JD
Zhang
Jie
J
Wang
Xu
X
Wang
Qing
Q
Yang
Shuang
S
Zhu
Tian-hui
TH
D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation
D055418:Bone Morphogenetic Protein 6; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D012333:RNA, Messenger; C066079:parathyroid hormone-related protein (1-108); D017868:Cyclic AMP-Dependent Protein Kinases
J Orthop Res. 2001 Jan;19(1):18-25
11332615
Endocrinology. 1996 Jun;137(6):2367-74
8641188
Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2732-6
1313566
Breast Cancer Res Treat. 2008 Oct;111(3):461-74
18030616
Oncogene. 2007 May 31;26(26):3777-88
17260025
J Clin Invest. 2007 Jul;117(7):1933-9
17607365
Cancer Res. 2006 Feb 15;66(4):2250-6
16489028
Int J Cancer. 1999 Jan 18;80(2):250-6
9935207
J Steroid Biochem Mol Biol. 2007 Jun-Jul;105(1-5):91-7
17574840
Int J Cancer. 2006 Jul 1;119(1):49-59
16450371
J Clin Endocrinol Metab. 2001 Apr;86(4):1788-94
11297619
Cancer. 2007 Sep 15;110(6):1313-20
17676588
Cancer Res. 2005 Sep 15;65(18):8274-85
16166304
J Bone Miner Res. 1999 Apr;14(4):475-82
10234567
Chin Med J (Engl). 2005 Oct 5;118(19):1629-36
16232348
Nat Med. 2002 Sep;8(9):995-1003
12185361
Genes Dev. 1996 Jul 1;10(13):1580-94
8682290
Vet Pathol. 2004 Mar;41(2):154-63
15017029
J Natl Cancer Inst. 2001 Feb 7;93(3):234-7
11158193
Brain Res. 2000 Jun 23;868(2):230-40
10854575
Matrix Biol. 2006 Mar;25(2):104-11
16455237
Endocr Relat Cancer. 2003 Jun;10(2):179-86
12790780
J Bone Miner Metab. 2008;26(6):642-7
18979165
J Biol Chem. 2001 Mar 16;276(11):7741-53
11108715
Cancer Res. 1991 Jun 1;51(11):3059-61
2032246
Int J Cancer. 1999 Dec 10;83(6):870-873
10602059
Cancer Res. 1990 Dec 1;50(23):7710-6
2253214
Br J Cancer. 2004 Mar 22;90(6):1293-4; author reply 1295
15026815