PO.PS01.01 · 人群科学
良性乳腺组织女性中循环胰岛素样生长因子-1和胰岛素样生长因子结合蛋白-3与间质标志物表达的关联
Associations of circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 with the expression of stromal markers in women with benign breast tissue
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摘要 Abstract
中文摘要
目的：乳腺组织微环境，特别是间质，对于维持正常组织结构十分重要，该环境内的改变可能影响乳腺癌（BCa）风险。常驻（正常）成纤维细胞是最丰富的间质细胞。在乳腺肿瘤中，癌相关成纤维细胞与更具侵袭性的表型和治疗耐药相关。胰岛素样生长因子（IGF）通路参与乳腺上皮细胞生长和细胞外基质重塑，并可能潜在地影响正常成纤维细胞。迄今为止，该关联尚未在流行病学研究中得到探索。我们首次考察了循环IGF-1和IGF结合蛋白-3（IGFBP-3）与成纤维细胞活化相关的乳腺间质标志物表达之间的关联：α-平滑肌肌动蛋白（αSMA）、腱生蛋白-C（TNC）、成纤维细胞活化蛋白（FAP）、钙周期蛋白（s100a6）和基质金属肽酶（MMP14）。
方法：本研究纳入了来自护士健康研究II（NHSII）队列的145名经活检确诊为新发良性乳腺疾病（BBD）的无癌女性。乳腺癌风险因素数据来自每两年一次的问卷调查。使用商品化抗体在组织芯片上进行间质标志物的免疫荧光（IF）染色（αSMA：1:400稀释；FAP：1:50；MMP14：1:150；TNC：1:200；s100a6：1:300）。对于每个芯，采用inForm v2.6.0量化阳性百分比。采用广义线性回归考察血浆IGF-1和IGFBP-3（连续对数转换值及四分位数）与每种间质标志物对数转换后阳性率之间的关联，并对乳腺癌风险因素和BBD亚型进行校正。
结果：在多变量分析中，无论以连续变量建模（beta=0.89，95%置信区间[CI] 0.07, 1.71）还是以四分位数建模（第4 vs. 第1四分位数的beta=0.82，CI 0.16, 1.48；p趋势=0.03），循环IGF-1均与s100a6表达呈正相关。循环IGFBP-3水平处于最高四分位数的女性似乎具有较低的TNC表达（beta=-2.51，95% CI -4.75, -0.27；p趋势=0.08）。未观察到αSMA、FAP和MMP14的关联。
结论：我们的研究结果提示循环IGF-1与s100a6呈正相关，IGFBP-3与TNC呈负相关，这与此前报道的IGF-1与乳腺癌风险正相关以及IGFBP-3与乳腺癌风险负相关一致。有必要开展未来研究以证实我们的发现。
查看英文原文 English abstract
Purpose: The breast tissue microenvironment, and specifically stroma, is important for maintaining the normal tissue structure, and alterations within this environment may influence breast cancer (BCa) risk. The resident (normal) fibroblasts are the most abundant stromal cells. In breast tumors, cancer-associated fibroblasts have been associated with more aggressive phenotypes, and resistance to treatment. The insulin-like growth factor (IGF) pathway is involved in breast epithelial cell growth and extracellular matrix remodeling and may potentially influence normal fibroblasts. To date this association has not been explored in epidemiological studies. We examined, for the first time, the associations of circulating IGF-1 and IGF binding protein-3 (IGFBP-3) with the expression of breast stromal markers related to fibroblast activation: alpha-smooth muscle actin (alphaSMA), tenascin-C (TNC), fibroblast activation protein (FAP), calcyclin (s100a6), and matrix metallo-peptidase (MMP14).
Methods: This study included 145 cancer-free women with incident biopsy-confirmed benign breast disease (BBD) from the Nurses' Health Study II (NHSII) cohort. The data on BCa risk factors were obtained from biennial questionnaires. Immunofluorescence (IF) of stromal markers was performed on tissue microarrays with commercial antibodies (alphaSMA: 1:400 dilution; FAP: 1:50; MMP14: 1:150; TNC: 1:200; s100a6: 1:300). For each core, the % positivity was quantified by inForm v2.6.0. Generalized linear regression was used to examine the associations of plasma IGF-1 and IGFBP-3 (continuous log-transformed and quartiles) with log-transformed positivity for each stromal marker, adjusted for BCa risk factors and BBD subtype.
Results: In multivariate analysis, circulating IGF-1 was positively associated with s100a6 expression both when modeled continuously (beta=0.89, 95% 95% Confidence Interval [CI] 0.07, 1.71) and as quartiles (beta for 4 th vs. 1 st quartile=0.82, CI 0.16, 1.48; p-trend=0.03). Women whose circulating IGFBP-3 levels were in the top quartile appeared to have lower expression of TNC (beta=-2.51, 95% CI -4.75, -0.27; p-trend=0.08). No associations were seen for alphaSMA, FAP, and MMP14.
Conclusion: Our findings suggest positive associations of circulating IGF-1 with s100a6 and inverse associations of IGFBP-3 with TNC, consistent with previously reported positive associations of IGF-1 and inverse associations of IGFBP-3 with BCa risk. Future studies are warranted to confirm our findings.
利益披露 Disclosure
L. Yaghjyan, None..
Y. J. Heng, None..
B. R. Sardella, None..
M. Ratcliffe, None..
R. M. Tamimi, None.