Mawer E B, Walls J, Howell A, Davies M, Ratcliffe W A, Bundred N J
University of Manchester Bone Disease Research Centre, Department of Medicine, Manchester Royal Infirmary, United Kingdom.
J Clin Endocrinol Metab. 1997 Jan;82(1):118-22. doi: 10.1210/jcem.82.1.3642.
1,25-dihydroxyvitamin D (1,25-(OH)2D) stimulates differentiation and controls proliferation in breast cancer cells. The role of endogenous 1,25-(OH)2D and its relation to PTH related protein (PTHrP) during the progression of breast cancer is not known; we therefore investigated these hormones in two studies. In a cross-sectional study of patients with breast cancer at different stages of disease, serum 1,25-(OH)2D levels (mean +/- SE) were highest in early disease (102 +/- 3.7 pmol/L), fell in normocalemic patients with bone metastases (52 +/- 5.3 pmol/L; P < 0.01), and were lowest in hypercalcemic patients (33 +/- 5.6 pmol/L; P < 0.001). PTHrP was detectable in the serum of only one normocalcemic patient with progressive metastases but was present in 11 of the 12 hypercalcemic patients, thus PTHrP did not stimulate 1,25-(OH)2D synthesis. In a 6-month longitudinal study of normocalcemic patients with bone metastases undergoing hormonal therapy, serum 1,25-(OH)2D concentrations fell in patients whose disease progressed (P = 0.0056), but remained constant in those who were stable or responded to treatment. These changes in 1,25-(OH)2D preceded clinical signs of progression and predicted disease response. In the progressive group, five of whom died during the study, 1,25-(OH)2D decreased between the initial and final samples, PTH fell significantly from 24.8 to 13.5 ng/L (P = 0.025), serum calcium rose from 2.27 to 2.39 mmol/L (P = 0.017), and the urinary calcium/creatinine ratio rose from 0.37 to 0.68 (P = 0.046). PTH and 1,25-(OH)2D were significantly correlated in the final samples from this group, Spearman's rank correlation = 0.80, P = 0.022. The results indicate that normocalcemia in these patients is maintained, at the expense of suppressing PTH and 1,25-(OH)2D, in the face of increased calcium released from lytic lesions in bone. Loss of the antiproliferative effects of 1,25-(OH)2D may then permit more rapid secondary growth of the tumor.
1,25 - 二羟维生素D（1,25-(OH)₂D）可刺激乳腺癌细胞分化并控制其增殖。内源性1,25-(OH)₂D在乳腺癌进展过程中的作用及其与甲状旁腺激素相关蛋白（PTHrP）的关系尚不清楚；因此，我们在两项研究中对这些激素进行了调查。在一项针对处于疾病不同阶段的乳腺癌患者的横断面研究中，血清1,25-(OH)₂D水平（均值±标准误）在疾病早期最高（102±3.7 pmol/L），在血钙正常但有骨转移的患者中下降（52±5.3 pmol/L；P<0.01），而在高钙血症患者中最低（33±5.6 pmol/L；P<0.001）。仅在一名血钙正常且有进行性转移的患者血清中检测到PTHrP，但在12名高钙血症患者中有11名检测到，因此PTHrP并未刺激1,25-(OH)₂D的合成。在一项对接受激素治疗的血钙正常且有骨转移的患者进行的为期6个月的纵向研究中，疾病进展的患者血清1,25-(OH)₂D浓度下降（P = 0.0056），但病情稳定或对治疗有反应的患者血清1,25-(OH)₂D浓度保持不变。1,25-(OH)₂D的这些变化先于疾病进展的临床体征并可预测疾病反应。在疾病进展组中，有5名患者在研究期间死亡，1,25-(OH)₂D在初始样本和最终样本之间下降，PTH从24.8显著降至13.5 ng/L（P = 0.025），血清钙从2.27 mmol/L升至2.39 mmol/L（P = 0.017），尿钙/肌酐比值从0.37升至0.68（P = 0.046）。该组最终样本中PTH与1,25-(OH)₂D显著相关，Spearman等级相关系数 = 0.80，P = 0.022。结果表明，面对骨溶解性病变释放的钙增加，这些患者通过抑制PTH和1,25-(OH)₂D来维持血钙正常。1,25-(OH)₂D抗增殖作用的丧失可能会使肿瘤更快地发生继发性生长。
