Altered Microenvironment Promotes Progression of Preinvasive Breast Cancer: Myoepithelial Expression of αvβ6 Integrin in DCIS Identifies High-risk Patients and Predicts Recurrence
Altered Microenvironment Promotes Progression of Preinvasive Breast Cancer: Myoepithelial Expression of αvβ6 Integrin in DCIS Identifies High-risk Patients and Predicts Recurrence
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DOI：
10.1158/1078-0432.ccr-13-1504
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发表时间：
2014-01-15
影响因子：
11.5
通讯作者：
Jones, J. Louise
中科院分区：
文献类型：
--
作者：
Allen, Michael D.;Thomas, Gareth J.;Jones, J. Louise
目的：本研究调查了导管原位癌（DCIS）肌上皮细胞中整合素α v β 6上调的功能和临床意义。通过免疫组织化学分析DCIS和具有相关侵袭的DCIS（n = 532）的存档样本的α v β 6表达，并在一个独立的，DCIS患者的随访结果。使用有和没有α v β 6表达的原代肌上皮细胞和肌上皮细胞系来测量α v β 6对体外和异种移植小鼠模型中肿瘤细胞系的生长和侵袭的影响。采用水貂肺上皮细胞（MLEC）试验和抗体抑制法确定TGF β信号通路的参与，采用真实的Time-PCR和酶谱法确定基质金属蛋白酶（MMP）-9的表达和活化。α v β 6的表达与侵袭性癌症的进展显著相关（P < 0.006），在一系列匹配的DCIS病例中，局部切除治疗的中位随访时间为114个月。我们表明avb 6的表达驱动肌上皮细胞促进体外肿瘤细胞侵袭，并增强体内乳腺肿瘤生长。α v β 6阳性肌上皮细胞的肿瘤促进作用依赖于TGF β驱动的MMP 9的上调，并可以通过抑制这一pathway.Conclusion：这些研究结果表明，DCIS中改变的肌上皮细胞预测疾病的进展和复发，并显示α v β 6对肌上皮细胞的上调通过TGF β上调MMP-9产生肿瘤促进功能。这些数据表明α v β 6的表达可用于对DCIS患者进行分层。(C)2013年AACR。
Purpose: This study investigated the functional and clinical significance of integrin alpha v beta 6 upregulation in myoepithelial cells of ductal carcinoma in situ (DCIS).Experimental Design: Archival samples of DCIS and DCIS with associated invasion (n = 532) were analyzed for expression of alpha v beta 6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, uniquecohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without alpha v beta 6 expression, were used to measure the effect of alpha v beta 6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGF beta signaling was established using mink lung epithelial cell (MLEC) assay and antibody inhibition, and expression and activation of matrix metalloproteinase (MMP)-9 established by Real Time-PCR and zymography.Results: Expression of alpha v beta 6 is significantly associated with progression to invasive cancer (P < 0.006) and with recurrence over a median follow-up of 114 months in a series of matched DCIS cases treated with local excision. We show that expression of avb6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of alpha v beta 6-positive myoepithelial cells is dependent on TGF beta-driven upregulation of MMP9 and can be abrogated by inhibiting this pathway.Conclusion: These findings indicate that altered myoepithelial cells in DCIS predict disease progression and recurrence and show that upregulation of alpha v beta 6 on myoepithelial cells generates a tumor promoter function through TGFb upregulation of MMP-9. These data suggest that expression of alpha v beta 6 may be used to stratify patients with DCIS. (C) 2013 AACR.