Oncol Rep：TGF-β通过MAPK促进乳腺癌侵袭转移

乳腺癌的发展和转移与转化生长因子-β（TGF-β）细胞因子的异常相关。在乳腺癌早期发展阶段，TGF-β呈现肿瘤抑制活性，能抑制细胞的增殖，诱导肿瘤细胞死亡，而在乳腺癌晚期阶段，TGF-β促进肿瘤细胞的侵袭和转移。

一直以来TGF-β的潜在致癌作用分子机制尚不完全清楚，近日Daroqui MC 等研究人员在Oncol Rep杂志上发表论文证实了TGF-β信号在癌症发生发展中的具体作用，研究者使用LM3乳腺腺癌细胞株探讨了TGF-β的致癌活性。激酶失活的TGF-β受体表达能降低肿瘤细胞基础水平以及TGF-β诱导的肿瘤细胞的侵袭。

信号传导分析研究表明，p38MAPK和MEK在TGF-β刺激肿瘤细胞运动和侵袭过程中发挥重要作用。TGF-β破坏上皮细胞的肌动蛋白结构（肌动蛋白结构主要支持细胞间的粘连），并增加线性肌动蛋白丝。阻断RAF-MEK信号通路能增强TGF-β诱导的肌动蛋白表达上调，而p38MAPK的抑制剂却能逆转上述效应。

此外，TGF-β刺激基质金属蛋白酶MMP-9的分泌。该研究表明，TGF-β有助于乳腺癌细胞的侵袭行为。MEK-ERK和p38 MAPK通路是TGF-β致癌的关键所在，也是干预治疗乳腺癌的潜在靶标。

doi:10.3892/or.2012.1813
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TGF-β autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression.

Daroqui MC, Vazquez P, Bal de Kier Joffé E, Bakin AV, Puricelli LI.

Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-β (TGF-β) cytokines. In early-stage breast cancers, TGF-β exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-β promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-β are not fully understood. The present study validates the role of TGF-β signaling in cancer progression and explores mediators of pro-oncogenic TGF-β activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-β receptors decreased both basal and TGF-β-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-β stimulation of cell motility and invasion. TGF-β disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-β. Blockade of Raf-MEK signaling enhanced TGF-β induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-β rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-β stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-β receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-β signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-β-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-β signaling.