FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer.
FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer.
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DOI：
10.1158/0008-5472.can-12-2962
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发表时间：
2013-03-15
期刊：
影响因子：
11.2
通讯作者：
Mani SA
中科院分区：
文献类型：
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作者：
Hollier BG;Tinnirello AA;Werden SJ;Evans KW;Taube JH;Sarkar TR;Sphyris N;Shariati M;Kumar SV;Battula VL;Herschkowitz JI;Guerra R;Chang JT;Miura N;Rosen JM;Mani SA
化疗抵抗和转移是乳腺癌相关死亡的主要原因。此外，癌症干细胞（CSCs）在癌症进展和治疗耐药性中起着关键作用。此前，研究发现，异常激活EMT可产生csc样细胞，从而使抗EMT策略成为治疗侵袭性乳腺癌的一种新的治疗选择。在这里，我们报道了转录因子FOXC2在多种EMT信号通路的诱导下以及在干细胞富集的派别中升高是间充质和干细胞特性的关键决定因素，在细胞诱导经历EMT和csc富集的乳腺癌细胞系中。更具体地说，使用慢病毒短发夹RNA抑制FOXC2表达导致间充质表型和相关的侵袭性和干细胞特性受到抑制，包括乳腺球形成能力和肿瘤起始能力降低。然而，FOXC2的过表达足以诱导转化的人乳腺上皮细胞的CSC特性和自发转移。此外，foxc2诱导的基因表达特征在含有EMT和CSC特征的低/基础B乳腺肿瘤亚型中丰富。在确定了PDGFR-β受FOXC2调控后，我们证明了fda批准的PDGFR抑制剂舒尼替尼靶向表达FOXC2的肿瘤细胞，导致CSC和转移性降低。因此，FOXC2或其相关基因表达程序可能为抗EMT为基础的治疗低cladin /基底B乳腺肿瘤或其他EMT/ csc富集肿瘤提供有效靶点。
Resistance to chemotherapy and metastases are the major causes of breast cancer-related mortality. Moreover, cancer stem cells (CSCs) play critical roles in cancer progression and treatment resistance. Previously, it was found that CSC-like cells can be generated by aberrant activation of EMT, thereby making anti-EMT strategies a novel therapeutic option for treatment of aggressive breast cancers. Here, we report that the transcription factor FOXC2 induced in response to multiple EMT signaling pathways as well as elevated in stem cell-enriched factions is a critical determinant of mesenchymal and stem cell properties, in cells induced to undergo EMT and CSC-enriched breast cancer cell lines. More specifically, attenuation of FOXC2 expression using lentiviral short hairpin RNA led to inhibition of the mesenchymal phenotype and associated invasive and stem cell properties, which included reduced mammosphere forming ability and tumor initiation. Whereas, overexpression of FOXC2 was sufficient to induce CSC properties and spontaneous metastasis in transformed human mammary epithelial cells. Furthermore, a FOXC2-induced gene expression signature was enriched in the claudin-low/basal B breast tumor subtype that contains EMT and CSC features. Having identified PDGFR-β to be regulated by FOXC2, we demonstrate that the FDA-approved PDGFR inhibitor, sunitinib, targets FOXC2-expressing tumor cells leading to reduced CSC and metastatic properties. Thus, FOXC2 or its associated gene expression program may provide an effective target for anti-EMT based therapies for the treatment of claudin-low/basal B breast tumors or other EMT/CSC-enriched tumors.