Chakrabarti J, Turley H, Campo L, Han C, Harris A L, Gatter K C, Fox S B
Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Br J Cancer. 2004 Aug 31;91(5):954-8. doi: 10.1038/sj.bjc.6602059.
DEC1, also known as SHARP-2 or Stra13, plays important roles in embryonic development, proliferation, apoptosis and cell differentiation in the mouse. DEC1 was recently identified as hypoxically induced in cDNA microarray studies of the human renal carcinoma cell line RCC4, to be regulated through hypoxia-inducible factor (HIF)-1alpha and via HIF-1alpha, able to block adipocyte differentiation. Nevertheless, its distribution and role in hypoxia and differentiation in human breast cancer are unknown. We therefore examined the pattern and level of expression of DEC1 using immunohistochemistry in whole tissue sections in normal, in situ and invasive breast carcinomas, and correlated the level of expression of DEC1 and clinicopathological factors and hypoxic tumour markers in 253 invasive carcinomas on tissue microarrays. We observed an increase in DEC1 expression during progression from normal to in situ and invasive carcinoma. Expression was not restricted to the tumour cell element but was also observed in endothelial, fibroblasts and inflammatory cells. There was a significant positive correlation between DEC1 and tumour grade (P=0.01), HIF-1alpha (P=0.04) and the hypoxically regulated gene angiogenin (P<0.0001), but no significant associations were observed with patient age (P=0.15), lymph node status (P=0.8), tumour size (P=0.3), oestrogen receptor (P=0.45), epidermal growth factor receptor (P=0.27) or Chalkley vessel count (P=0.45). There was no difference in relapse-free (P=0.84) or overall (P=0.78) survival. These findings suggest that DEC1 plays an important role in the progression to invasive breast cancer and that it may provide a mechanism by which hypoxia blocks tumour differentiation, and may contribute to a more aggressive phenotype. Reversing this phenotype may alter the biological behaviour of individual tumours.
DEC1，也被称为SHARP - 2或Stra13，在小鼠的胚胎发育、增殖、凋亡和细胞分化过程中发挥着重要作用。最近在人肾癌细胞系RCC4的cDNA微阵列研究中发现，DEC1是低氧诱导产生的，它通过缺氧诱导因子（HIF）-1α进行调控，并且能够通过HIF - 1α阻断脂肪细胞分化。然而，其在人乳腺癌低氧和分化过程中的分布及作用尚不清楚。因此，我们采用免疫组织化学方法，检测了DEC1在正常乳腺组织、原位癌和浸润性乳腺癌全组织切片中的表达模式和水平，并将253例浸润性癌组织芯片上DEC1的表达水平与临床病理因素及低氧肿瘤标志物进行了相关性分析。我们观察到，从正常乳腺组织发展到原位癌和浸润性癌的过程中，DEC1的表达增加。其表达不仅局限于肿瘤细胞成分，在内皮细胞、成纤维细胞和炎性细胞中也可观察到。DEC1与肿瘤分级（P = 0.01）、HIF - 1α（P = 0.04）以及低氧调控基因血管生成素（P < 0.0001）之间存在显著正相关，但与患者年龄（P = 0.15）、淋巴结状态（P = 0.8）、肿瘤大小（P = 0.3）、雌激素受体（P = 0.45）、表皮生长因子受体（P = 0.27）或Chalkley血管计数（P = 0.45）之间未观察到显著相关性。在无复发生存率（P = 0.84）或总生存率（P = 0.78）方面没有差异。这些研究结果表明，DEC1在浸润性乳腺癌的进展过程中发挥着重要作用，它可能提供了一种低氧阻断肿瘤分化的机制，并可能导致更具侵袭性的表型。逆转这种表型可能会改变个体肿瘤的生物学行为。
