Fascin介导的TGF-β信号环路在基底细胞样乳腺癌侵袭转移中的机制研究

The basal-like breast cancer (BLBC) is a subtype of breast cancer characterized by gene expression profile similar to that of basal myoepithelial cells of the breast, and accounts for about 15-25% of breast cancers . Since BLBC typically do not express hormone receptors or Her2 , they are poorly responsive to currently available targeted therapies , leaving this subgroup of patients with few systematic treatment options other than cytotoxic chemotherapy. Moreover, the BLBC cancer has more aggressive clinical course and is especially prone to regional and distant metastasis . Consequently this subset of breast cancer patients is disproportionally associated with cancer-related deaths . There is an urgent need to understand the molecular mechanisms underlying BLBC progression, and to identify novel therapeutic targets for BLBC. Recent preliminary studies from our group and others suggest that fascin is an attractive intervention target for metastatic BLBC. Fascin is overexpressed in the BLBC subgroup and plays a causal role in breast cancer lung metastasis. The overexpression of fascin in BLBC is mediated by transforming growth factor β (TGFβ), which promotes fascin overexpression through the canonical TGFβ-Smad signaling axis. Our preliminary data support a fascin–TGFβ signaling loop during BLBC metastasis. We propose that fascin acts as both “sensor” and “remodeler” of the pro-metastasis BLBC microenvironment. As a sensor fascin expression levels increase in response to elevated TGFβ levels in the BLBC microenvironment; as a remodeler fascin promotes the formation of invadopodia and secretion of matrix metalloproteinase to remodel the extracellular matrix (ECM) and to release more active TGFβ from the BLBC microenvironment. In this proposal we will define the fascin-TGFβ signaling loop in BLBC lung metastasis. Anticipated findings from this two aims will bring significant insight into the mechanistic roles of fascin in BLBC progression. We will also define the structural basis underlying fascin-mediated metastatic colonization, and explore novel strategies targeting fascin in BLBC.

基底细胞样乳腺癌（BLBC）是乳腺癌的一种亚型，容易产生局部侵袭或远处转移，加之通常不表达ER、PR或者Her2，药物及靶向治疗不敏感，因此，患者预后较差。我们的初步研究显示Fascin 在BLBC亚型的乳腺癌中过表达，且与预后不良密切相关，在BLBC细胞中降低Fascin的表达能在体外抑制细胞侵袭，并且在小鼠模型中抑制肺转移，这些数据表明Fascin在BLBC的肺转移中起着关键作用。预实验提示TGFβ-Smad信号通路能够诱导Fascin的表达，进而促进侵袭伪足的形成，而Fascin介导的伪足形成和活化又进一步释放和激活肿瘤微环境中的TGFβ，因此我们提出假设，Fascin介导的TGF-β信号环路促进了BLBC侵袭转移，本课题拟深入研究其具体的分子机制，此外，针对Fascin的核心地位，我们进一步分析它相关的结构基础和活性位点，探讨Fascin特异性抑制物，发现BLBC治疗的新靶点。

基底细胞样乳腺癌（BLBC）是乳腺癌的一种亚型，容易产生局部侵袭或远处转移，加之通常不表达ER、PR或者Her2，药物及靶向治疗不敏感，因此，患者预后较差。我们的初步研究显示Fascin 在BLBC亚型的乳腺癌中过表达，且与预后不良密切相关，在BLBC细胞中降低Fascin的表达能在体外抑制细胞侵袭，并且在小鼠模型中抑制肺转移，这些数据表明Fascin在BLBC的肺转移中起着关键作用。预实验提示TGFβ-Smad信号通路能够诱导Fascin的表达，进而促进侵袭伪足的形成，而Fascin介导的伪足形成和活化又进一步释放和激活肿瘤微环境中的TGFβ，因此我们提出假设，Fascin介导的TGF-β信号环路促进了BLBC侵袭转移，本课题拟深入研究其具体的分子机制，此外，针对Fascin的核心地位，我们进一步分析它相关的结构基础和活性位点，探讨Fascin特异性抑制物，发现BLBC治疗的新靶点。