Department of Pathological Sciences, Biological Sciences Center, Londrina State University, Londrina, PR, 86057-970, Brazil.
Department of Clinical Research, Londrina Cancer Hospital, Londrina, PR, 86015-520, Brazil.
Breast Cancer Res Treat. 2019 Nov;178(1):207-219. doi: 10.1007/s10549-019-05370-1. Epub 2019 Jul 30.
Transforming growth factor beta (TGFβ) has paradoxical effects in breast cancer (BC), inhibiting initial tumors while promoting aggressive ones. A polymorphism on TGFBR2 promoter region (G-875A, rs3087465) increases TGFβ type II receptor expression and is protective against cancer. Previously, we have shown that TGFB1 variants have subtype-specific roles in BC. This work sought to investigate the association between TGFBR2 and susceptibility and clinicopathological features in BC subgroups.
TGFBR2 G-875A was analyzed through PCR-RFLP in 388 BC patients and 405 neoplasia-free women. Case-control analyses as well as interaction with TGFB1 haplotypes previously associated with BC were tested through age-adjusted logistic regression. Correlations between G-875A and clinicopathological parameters were assessed through Kendall's Tau-b test. All statistical tests were two-tailed (α = 0.05).
TGFBR2 G-875A was protective against BC in additive, genotypic, and dominant models. In subgroup-stratified analyses, these effects were greater in hormonal receptor-positive and luminal-A tumors, but were not significant in other subgroups. Logistic models including TGFB1 variants showed that in luminal-A tumors, G-875A retained its significance while TGFB1 haplotype showed a trend towards significance; otherwise, in HER2 tumors TGFB1 variants remained significant while TGFBR2 showed a trend for association. There was no interaction between these genes. In correlation analyses, G-875A positively correlated with histopathological grade in total sample, and a trend towards significance was observed in triple-negative BCs.
These results indicate that G-875A is a protective factor against BC, especially from luminal-A subtype, but may promote anaplasia in established tumors, consistent with TGFβ signaling roles in BC.
转化生长因子β（TGFβ）在乳腺癌（BC）中具有矛盾的作用，抑制初始肿瘤的同时促进侵袭性肿瘤的发展。TGFBR2 启动子区域的一个多态性（G-875A，rs3087465）增加了 TGFβ Ⅱ型受体的表达，并具有抗癌作用。此前，我们已经表明，TGFB1 变体在 BC 中具有亚类特异性作用。这项工作旨在研究 TGFBR2 与 BC 亚组的易感性和临床病理特征之间的关系。
通过 PCR-RFLP 分析 388 例 BC 患者和 405 例非肿瘤女性的 TGFBR2 G-875A。通过年龄调整的逻辑回归测试病例对照分析以及与先前与 BC 相关的 TGFB1 单倍型的相互作用。通过 Kendall's Tau-b 检验评估 G-875A 与临床病理参数之间的相关性。所有统计检验均为双侧（α=0.05）。
TGFBR2 G-875A 在加性、基因型和显性模型中对 BC 具有保护作用。在亚组分层分析中，这些效应在激素受体阳性和 luminal-A 肿瘤中更大，但在其他亚组中不显著。包含 TGFB1 变体的逻辑模型表明，在 luminal-A 肿瘤中，G-875A 仍然具有显著性，而 TGFB1 单倍型则具有显著趋势；否则，在 HER2 肿瘤中，TGFB1 变体仍然具有显著性，而 TGFBR2 则具有相关性趋势。这些基因之间没有相互作用。在相关性分析中，G-875A 在总样本中与组织病理学分级呈正相关，在三阴性 BC 中呈显著趋势。
这些结果表明，G-875A 是 BC 的保护因素，特别是来自 luminal-A 亚型，但可能促进已建立的肿瘤的间变，与 TGFβ 在 BC 中的信号作用一致。
