Tinholt Mari, Vollan Hans Kristian Moen, Sahlberg Kristine Kleivi, Jernström Sandra, Kaveh Fatemeh, Lingjærde Ole Christian, Kåresen Rolf, Sauer Torill, Kristensen Vessela, Børresen-Dale Anne-Lise, Sandset Per Morten, Iversen Nina
Department of Medical Genetics, Oslo University Hospital and University of Oslo, BOX 4956, Nydalen, Oslo, N-0424, Norway.
Department of Haematology and Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
Breast Cancer Res. 2015 Mar 26;17(1):44. doi: 10.1186/s13058-015-0548-5.
Hypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer.
The relationship between tumor messenger RNA (mRNA) expression and plasma levels of TF and TFPI (α and β), tagging single nucleotide polymorphisms (tagSNPs) in F3 (TF) (n=6) and TFPI (n=18), and clinicopathological characteristics and molecular tumor subtypes were explored in 152 treatment naive breast cancer patients. The effect of tumor expressed TF and TFPIα and TFPIβ on survival was investigated in a merged breast cancer dataset of 1881 patients.
Progesterone receptor negative patients had higher mRNA expression of total TFPI (α+β) (P=0.021) and TFPIβ (P=0.014) in tumors. TF mRNA expression was decreased in grade 3 tumors (P=0.003). In plasma, total TFPI levels were decreased in patients with larger tumors (P=0.013). SNP haplotypes of TFPI, but not TF, were associated with specific clinicopathological characteristics like tumor size (odds ratio (OR) 3.14, P=0.004), triple negativity (OR 2.4, P=0.004), lymph node spread (OR 3.34, P=0.006), and basal-like (OR 2.3, P=0.011) and luminal B (OR 3.5, P=0.005) molecular tumor subtypes. Increased expression levels of TFPIα and TFPIβ in breast tumors were associated with better outcome in all tumor subtypes combined (P=0.007 and P=0.005) and in multiple subgroups, including lymph node positive subjects (P=0.006 and P=0.034).
This study indicates that genetic and phenotypic variation of both TFPIα and TFPIβ, more than TF, are markers of cancer progression. Together with the previously demonstrated tumor suppressor effects of TFPI, the beneficial effect of tumor expressed TFPI on survival, renders TFPI as a potential anticancer agent, and the clinical significance of TFPI in cancer deserves further investigation.
恶性肿瘤中的高凝状态会增加血栓形成的风险，但也与癌症进展有关。实验研究表明，组织因子（TF）和组织因子途径抑制剂（TFPI）分别作为肿瘤促进剂和抑制剂参与癌症生物学过程，但其临床意义尚不清楚。在此，我们旨在研究TF和TFPI基因及表型多样性在乳腺癌中的临床相关性。
在152例未经治疗的乳腺癌患者中，探讨肿瘤信使核糖核酸（mRNA）表达与TF和TFPI（α和β）血浆水平之间的关系、F3（TF）（n = 6）和TFPI（n = 18）中的标签单核苷酸多态性（tagSNP）以及临床病理特征和分子肿瘤亚型。在一个包含1881例患者的合并乳腺癌数据集中，研究肿瘤表达的TF、TFPIα和TFPIβ对生存的影响。
孕激素受体阴性患者肿瘤中总TFPI（α + β）（P = 0.021）和TFPIβ（P = 0.014）的mRNA表达较高。3级肿瘤中TF mRNA表达降低（P = 0.003）。在血浆中，肿瘤较大的患者总TFPI水平降低（P = 0.013）。TFPI的单核苷酸多态性单倍型而非TF与特定临床病理特征相关，如肿瘤大小（优势比（OR）3.14，P = 0.004）、三阴性（OR 2.4，P = 0.004）、淋巴结转移（OR 3.34，P = 0.006）以及基底样（OR 2.3，P = 0.011）和管腔B型（OR 3.5，P = 0.005）分子肿瘤亚型。乳腺肿瘤中TFPIα和TFPIβ表达水平升高与所有肿瘤亚型联合（P = 0.007和P = 0.005）以及包括淋巴结阳性受试者在内的多个亚组（P = 0.006和P = 0.034）的更好预后相关。
本研究表明，与TF相比，TFPIα和TFPIβ的基因和表型变异是癌症进展的标志物。结合先前证明的TFPI的肿瘤抑制作用，肿瘤表达的TFPI对生存的有益作用使TFPI成为一种潜在的抗癌剂，TFPI在癌症中的临床意义值得进一步研究。
