Coexpression of parathyroid hormone related protein and its receptor in early breast cancer predicts poor patient survival.
OBJECTIVE
Parathyroid hormone-related protein (PTHRP) is in part responsible for the clinical syndrome of hypercalcaemia of malignancy and has been implicated as an important factor in the development of bone metastases. The aim of this study was to determine the coexpression of PTHRP and its receptor in early breast cancer (EBC) and bone metastases (BM), and correlate these findings to clinical outcome.


METHODS
Samples of surgically excised EBC (n = 176) and BM (n = 43) were collected and stored in liquid nitrogen. PTHRP protein was determined using immunohistochemistry and receptor mRNA using in situ hybridization (n = 107) or semiquantitative reverse transcription-PCR (n = 69).


RESULTS
PTHRP protein was expressed in 115 of 170 (68%) EBC compared with 100% of BM (P < 0.001), whereas its receptor mRNA was expressed in 88 of 176 (50%) EBC compared with 35 of 43 (81%) BM (P < 0.001). Coexpression of both PTHRP and its receptor was present in 62 EBC samples (37%) and in 35 BM samples (81%; P < 0.001). The PTHRP receptor correlated well with increasing patient age, but not with tumor size, grade, estrogen receptor, progesterone receptor, or lymph node status. Individually PTHRP and PTHRP receptor both correlated well with a reduced disease-free survival (P < 0.004) and receptor alone with reduced overall survival (P < 0.003). Coexpression of both PTHRP and receptor predicted the worst clinical outcome at 5 years, with a mortality rate of 20 of 62 (32%) compared with the ligand and receptor-negative group with 2 of 32 (6%; P < 0.004).


CONCLUSIONS
Overall these results show that the PTHRP receptor is expressed more frequently in BM than EBC, and is associated with poor clinical outcome and survival.
Linforth
Richard
R
Academic Department of Surgery, Division of Cancer Studies, Schools of Medicine, University of Manchester, Manchester M23 9LT, United Kingdom.
Anderson
Neil
N
Hoey
Richard
R
Nolan
Tania
T
Downey
Sarah
S
Brady
Gerard
G
Ashcroft
Linda
L
Bundred
Nigel
N
D000368:Aged; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D015342:DNA Probes; D018076:DNA, Complementary; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1; D011960:Receptors, Estrogen / Q000378:metabolism; D018016:Receptors, Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D015342:DNA Probes; D018076:DNA, Complementary; D019394:Ki-67 Antigen; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D011960:Receptors, Estrogen; D018016:Receptors, Parathyroid Hormone; D011980:Receptors, Progesterone