MYC Is a Crucial Mediator of TGFβ-Induced Invasion in Basal Breast Cancer.
MYC Is a Crucial Mediator of TGFβ-Induced Invasion in Basal Breast Cancer.
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DOI：
10.1158/0008-5472.can-15-3465
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发表时间：
2016-06-15
期刊：
影响因子：
11.2
通讯作者：
Radisky DC
中科院分区：
文献类型：
--
作者：
Cichon MA;Moruzzi ME;Shqau TA;Miller E;Mehner C;Ethier SP;Copland JA;Radisky ES;Radisky DC
基底亚型乳腺癌的预后特别差，具有高侵袭性和对大多数靶向治疗的抗性。TGFβ和MYC驱动基底乳腺癌的中心特征：TGFβ是驱动细胞侵袭和转移的自分泌和旁分泌信号传导因子，MYC是在许多癌症类型中上调的细胞增殖的中心调节因子。我们在这里表明，MCF 10A基底乳腺细胞中MYC的遗传或药理学抑制导致对TGFβ刺激的侵袭和转移的敏感性增加，并且还表明该信号传导回路依赖于SRC的激活。对人类乳腺癌数据集的分析和对乳腺癌细胞系的额外实验进一步表明了这种信号环在基底乳腺癌中的相关性，而不是在管腔乳腺癌中的相关性。我们的研究结果表明，在对基底乳腺癌患者使用MYC治疗性抑制剂时应采取预防措施，因为这可能导致转移增加;然而，同时对这些患者进行SRC和MYC的药理学抑制可以促进MYC抑制的抗增殖作用，同时阻断随之而来的转移促进作用。
Basal subtype breast cancers have a particularly poor prognosis, with high invasiveness and resistance to most targeted therapies. TGFβ and MYC drive central features of basal breast cancer: TGFβ is an autocrine and paracrine signaling factor that drives cell invasion and metastasis, and MYC is a central regulator of cellular proliferation that is upregulated in many cancer types. We show here that genetic or pharmacological inhibition of MYC in MCF10A basal breast cells results in increased sensitivity to TGFβ-stimulated invasion and metastasis, and also show that this signaling loop is dependent on activation of SRC. Analysis of human breast cancer datasets and additional experiments with breast cancer cell lines further suggest the relevance of this signaling loop in basal, but not luminal, breast cancers. Our results imply precaution should be taken when utilizing therapeutic inhibitors of MYC with basal breast cancer patients as this could lead to increased metastasis; however, simultaneous pharmacological inhibition of SRC and MYC for these patients could facilitate the anti-proliferative effects of MYC inhibition while blocking the consequent promotion of metastasis.