Linforth Richard, Anderson Neil, Hoey Richard, Nolan Tania, Downey Sarah, Brady Gerard, Ashcroft Linda, Bundred Nigel
Academic Department of Surgery, Division of Cancer Studies, Schools of Medicine, University of Manchester, Manchester M23 9LT, United Kingdom.
Clin Cancer Res. 2002 Oct;8(10):3172-7.
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.
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).
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).
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.
甲状旁腺激素相关蛋白（PTHRP）在恶性肿瘤高钙血症临床综合征中起部分作用，并且被认为是骨转移发生发展的一个重要因素。本研究的目的是确定PTHRP及其受体在早期乳腺癌（EBC）和骨转移（BM）中的共表达情况，并将这些发现与临床结局相关联。
收集手术切除的EBC样本（n = 176）和BM样本（n = 43），并储存在液氮中。使用免疫组织化学法测定PTHRP蛋白，使用原位杂交（n = 107）或半定量逆转录聚合酶链反应（n = 69）测定受体mRNA。
170例EBC中有115例（68%）表达PTHRP蛋白，而BM中表达率为100%（P < 0.001）；176例EBC中有88例（50%）表达其受体mRNA，而43例BM中有35例（81%）表达（P < 0.001）。62例EBC样本（37%）和35例BM样本（81%；P < 0.001）中存在PTHRP及其受体的共表达。PTHRP受体与患者年龄增加密切相关，但与肿瘤大小、分级、雌激素受体、孕激素受体或淋巴结状态无关。单独来看，PTHRP和PTHRP受体均与无病生存期缩短密切相关（P < 0.004），单独受体与总生存期缩短相关（P < 0.003）。PTHRP和受体的共表达预测5年时临床结局最差，62例中有20例（32%）死亡，而配体和受体阴性组32例中有2例（6%）死亡（P < 0.004）。
总体而言，这些结果表明PTHRP受体在BM中的表达频率高于EBC，并且与不良临床结局和生存期相关。
