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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2020, Vol. 14 ›› Issue (01) : 18 -22. doi: 10.3877/cma.j.issn.1674-0807.2020.01.007

所属专题： 文献；

论著

转录因子叉头框C1在三阴性乳腺癌中的表达及其与患者预后的关系
沈松杰1, 任新瑜2, 徐雅莉1, 周易冬1, 孙强1,†()   
  1. 1. 100730　中国医学科学院北京协和医学院北京协和医院乳腺外科
    2. 100730　中国医学科学院病理科
  • 收稿日期:2019-09-27 出版日期:2020-02-01
  • 通信作者: 孙强
  • 基金资助:
    北京市自然科学基金资助项目(7172168); 中央高校基本科研业务费专项资金资助项目(3332018020)

Expression and prognostic value of transcription factor forkhead box C1 in triple negative breast cancer

Songjie Shen1, Xinyu Ren2, Yali Xu1, Yidong Zhou1, Qiang Sun1,†()   

  1. 1. Department of Breast Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
    2. Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
  • Received:2019-09-27 Published:2020-02-01
  • Corresponding author: Qiang Sun
  • About author:
    Corresponding author: Sun Qiang, Email:
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沈松杰, 任新瑜, 徐雅莉, 周易冬, 孙强. 转录因子叉头框C1在三阴性乳腺癌中的表达及其与患者预后的关系[J]. 中华乳腺病杂志(电子版), 2020, 14(01): 18-22.

Songjie Shen, Xinyu Ren, Yali Xu, Yidong Zhou, Qiang Sun. Expression and prognostic value of transcription factor forkhead box C1 in triple negative breast cancer[J]. Chinese Journal of Breast Disease(Electronic Edition), 2020, 14(01): 18-22.

目的

探讨转录因子叉头框C1(FOXC1)在三阴性乳腺癌(TNBC)中的表达及其与患者预后的关系。

方法

回顾性分析2002年3月至2012年3月在中国医学科学院北京协和医学院北京协和医院进行乳腺癌改良根治术或保留乳房手术的TNBC患者临床资料。患者随访截止日期为2019年3月1日。选择符合纳入、排除标准且有复发、转移或随访10年以上无复发、转移的患者，提取乳腺癌原发灶组织RNA进行分析。排除标本不足或RNA提取质控不达标的患者后，最终有59例(27例无复发、转移，32例复发、转移)标本通过定量反转录聚合酶链反应(qRT-PCR)检测FOXC1表达量。患者临床特征的分析采用χ2检验或非参数检验(Mann-Witney U检验)；复发、转移组与无复发、转移组患者年龄及FOXC1表达量(ΔCT值)的比较采用t检验；多因素分析采用Cox比例风险回归模型；患者生存率的比较采用log-rank检验。

结果

复发、转移组与无复发、转移组患者比较，年龄、肿瘤大小、组织学分级、P53、Ki67表达和脉管癌栓的差异均无统计学意义(t＝－0.226，P＝0.165；χ2＝1.923，P＝0.165；Z＝－1.694，P＝0.090；χ2＝0.336，P＝0.562；P＝1.000；P＝1.000)，但复发、转移组患者腋窝淋巴结转移的比例更高[75.0% (24/32)比40.7% (11/27)，χ2＝7.123，P＝0.008]。复发、转移组FOXC1表达量是无复发、转移组的2.7倍，2组比较，差异有统计学意义(ΔCT值：4.064±1.392比5.510±1.581，t＝3.737，P<0.001)。多因素分析提示，FOXC1高表达是TNBC患者无复发生存(RFS)的独立危险因素(HR＝2.531，95%CI：1.211～5.290，P＝0.014)，而临床上常用的病理指标，仅淋巴结转移与RFS相关(HR＝2.453，95%CI：1.093～5.504，P＝0.030)。FOXC1高表达的TNBC患者，其RFS和OS都更差(RFS：χ2＝8.419，P＝0.004；OS：χ2＝4.644，P＝0.031)。

结论

FOXC1高表达患者出现复发、转移的风险显著增加，可以作为TNBC预后细分的有用指标。

关键词: 转录因子, 乳腺肿瘤, 预后
Objective

To investigate the expression of the transcription factor forkhead box C1 (FOXC1) in triple negative breast cancer (TNBC) and its prognostic value.

Methods

TNBC patients who received modified radical mastectomy or breast-conserving surgery in the Peking Union Medical College Hospital between March 2002 and March 2012 were retrospectively analyzed in this study. The last follow-up date was March 1, 2019. Archived specimens of primary breast cancer were collected for RNA extraction from those who met the inclusion and exclusion criteria and were recurrence-free for more than 10 years, and those who had an early recurrence or metastasis. RNA extraction was successful in specimens of 59 patients (27 without recurrence or metastasis, and 32 with recurrence or metastasis), excluding those with insufficient specimens or failure in quality control of RNA extraction. The FOXC1 mRNA expression of the specimens was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The χ2 test or nonparametric test (Mann-Witney U test) was used in the comparison of enumeration data and the t test was used in the comparison of age and FOXC1 expression level (ΔCT value) between the recurrent and the non-recurrent groups. Multivariate analysis was performed by the Cox’s proportional hazards regression model. The survival rate was compared by the log-rank test.

Results

There was no significant difference in age, tumor size, histological grade, P53 status, Ki67 expression and peritumoral vascular invasion between the recurrent and non-recurrent groups (t=-0.226, P=0.165; χ2=1.923, P=0.165; Z=-1.694, P=0.090; χ2=0.336, P=0.562; P=1.000; P=1.000). However, the rate of lymph node metastasis was higher in the recurrent group than in the non-recurrent group[75.0% (24/32) vs 40.7% (11/27), χ2=7.123, P=0.008]. The expression level of FOXC1 in the recurrent group was 2.7 times as high as that in the non-recurrent group (ΔCT value: 4.064±1.392 vs 5.510±1.581, t=3.737, P<0.001). Multivariate analysis showed that high FOXC1 expression was an independent risk factor of recurrence-free survival (RFS) in TNBC patients (HR=2.531, 95%CI: 1.211-5.290, P=0.014). The traditional pathological factors, except lymph node status (HR=2.453, 95%CI: 1.093-5.504, P=0.030), did not reach significant difference to predict recurrence and metastasis. The patients with high expression of FOXC1 had worse RFS and OS (RFS: χ2=8.419, P=0.004; OS: χ2=4.644, P=0.031).

Conclusion

Patients with high expression of FOXC1 are at increased risk of recurrence and metastasis, so FOXC1 can be used as a candidate prognostic marker for TNBC patients.

Key words: Transcription factors, Breast neoplasms, Prognosis
表1 乳腺癌患者无复发生存影响因素的Cox比例风险回归模型变量赋值表
因素 变量 变量分类及赋值
肿瘤大小 X1 ≤2.0 cm＝0，>2.0 cm＝1
组织学分级 X2 1级和2级＝0，3级＝1
Ki67表达 X3 <20%＝0，≥20%＝1
腋窝淋巴结转移 X4 无＝0，有＝1
FOXC1表达 X5 低表达＝0，高表达＝1
无复发生存 Y 无复发、转移＝0，复发、转移＝1
表2 59例乳腺癌患者的临床病理特征(例)
临床病理特征 无复发、转移组(n＝27) 复发、转移组(n＝32) 统计量 P值
肿瘤大小 ? ? χ2＝1.923 0.165
? ≤2.0 cm 15 12 ? ?
? >2.0 cm 12 20 ? ?
组织学分级 ? ? Z＝－1.694 0.090
? 1级 2 0 ? ?
? 2级 10 8 ? ?
? 3级 15 24 ? ?
P53 ? ? χ2＝0.336 0.562
? 阴性 13 13 ? ?
? 阳性 14 19 ? ?
Ki67表达 ? ? ? 1.000a
? <20% 5 5 ? ?
? ≥20% 22 27 ? ?
脉管癌栓 ? ? ? 1.000a
? 无 25 30 ? ?
? 有 2 2 ? ?
腋窝淋巴结转移 ? ? χ2＝7.123 0.008
? 否 16 8 ? ?
? 是 11 24 ? ?
表3 采用Cox比例风险回归模型分析乳腺癌患者无复发生存的相关因素(n＝59)
变量 单因素分析 多因素分析
HR 95%CI P值 HR 95%CI P值
肿瘤大小 1.667 0.814～3.414 0.162 ? ? ?
组织学分级 1.856 0.833～4.135 0.130 ? ? ?
Ki67表达 1.044 0.402～2.713 0.929 ? ? ?
腋窝淋巴结转移 2.751 1.232～6.141 0.014 2.453 1.093～5.504 0.030
FOXC1表达 2.804 1.348～5.835 0.006 2.531 1.211～5.290 0.014
图1 FOXC1低表达组与高表达组三阴性乳腺癌患者的生存曲线　a图为2组患者间无复发生存曲线比较；b图为2组患者间总生存曲线比较
[1]
Waks AG, Winer EP. Breast cancer treatment: a review [J]. JAMA, 2019，321(3)：288-300.
[2]
Bianchini G, Balko JM, Mayer IA, et al. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease [J]. Nat Rev Clin Oncol, 2016，13(11)：674-690.
[3]
沈松杰，孙强，周易冬，等. 三阴性乳腺癌预后相关因素分析 [J]. 中华外科杂志， 2013，51(11)：1000-1004.
[4]
Shen S, Sun Q, Liang Z, et al. A prognostic model of triple-negative breast cancer based on mir-27b-3p and node status [J]. PLoS One, 2014，9(6)：e100664.
[5]
Park YH, Lee SJ, Cho EY, et al. Clinical relevance of tnm staging system according to breast cancer subtypes [J]. Ann Oncol, 2011，22(7)：1554-1560.
[6]
Gilding LN, Somervaille TCP. The diverse consequences of FOXC1 deregulation in cancer [J]. Cancers (Basel), 2019，11(2)：184.
[7]
Han B, Bhowmick N, Qu Y, et al. Foxc1: An emerging marker and therapeutic target for cancer [J]. Oncogene, 2017，36(28)：3957-3963.
[8]
Han B, Zhou B, Qu Y, et al. Foxc1-induced non-canonical WNT5A-MMP7 signaling regulates invasiveness in triple-negative breast cancer [J]. Oncogene, 2018，37(10)：1399-1408.
[9]
Elian FA, Yan E, Walter MA. Foxc1, the new player in the cancer sandbox [J]. Oncotarget, 2018，9(8)：8165-8178.
[10]
Pan H, Peng Z, Lin J, et al. Forkhead box C1 boosts triple-negative breast cancer metastasis through activating the transcription of chemokine receptor-4 [J]. Cancer Sci, 2018，109(12)：3794-3804.
[11]
Wang J, Ray PS, Sim MS, et al. Foxc1 regulates the functions of human basal-like breast cancer cells by activating nf-kappab signaling [J]. Oncogene, 2012，31(45)：4798-4802.
[12]
Chung S, Jin Y, Han B, et al. Identification of egf-nf-kappab-foxc1 signaling axis in basal-like breast cancer [J]. Cell Commun Signal, 2017，15(1)：22.
[13]
Yu-Rice Y, Jin Y, Han B, et al. Foxc1 is involved in ERα silencing by counteracting GATA3 binding and is implicated in endocrine resistance [J]. Oncogene, 2016，35(41)：5400-5411.
[14]
Wang J, Xu Y, Li L, et al. Foxc1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer [J]. Cancer Med, 2017，6(1)：275-287.
[15]
Hirukawa A, Smith HW, Zuo D, et al. Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program [J]. Nat Commun, 2018，9(1)：2547.
[16]
Jensen TW, Ray T, Wang J, et al. Diagnosis of basal-like breast cancer using a foxc1-based assay [J]. J Natl Cancer Inst, 2015，107(8)：djv148.
[17]
Zon G, Barker MA, Kaur P, et al. Formamide as a denaturant for bisulfite conversion of genomic DNA: Bisulfite sequencing of the GSTPi and RARbeta2 genes of 43 formalin-fixed paraffin-embedded prostate cancer specimens [J]. Anal Biochem, 2009，392(2)：117-125.
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