Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, United States of America.
PLoS One. 2010 Apr 28;5(4):e10365. doi: 10.1371/journal.pone.0010365.
Recent studies suggested that induction of epithelial-mesenchymal transition (EMT) might confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGFbeta is a potent inducer of EMT and has been shown to promote tumor progression in various breast cancer cell and animal models.
We report that chemotherapeutic drug doxorubicin activates TGFbeta signaling in human and murine breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced generation of cells with stem cell phenotype in murine 4T1 breast cancer cells in vitro, which were significantly inhibited by a TGFbeta type I receptor kinase inhibitor (TbetaRI-KI). We investigated the potential synergistic anti-tumor activity of TbetaR1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and TbetaRI-KI enhanced the efficacy of doxorubicin in reducing tumor growth and lung metastasis in the 4T1 orthotopic xenograft model in comparison to single treatments. Doxorubicin treatment alone enhanced metastasis to lung in the human breast cancer MDA-MB-231 orthotopic xenograft model and metastasis to bone in the 4T1 orthotopic xenograft model, which was significantly blocked when TbetaR1-KI was administered in combination with doxorubicin.
These observations suggest that the adverse activation of TGFbeta pathway by chemotherapeutics in the cancer cells together with elevated TGFbeta levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. Our results indicate that the combination treatment of doxorubicin with a TGFbeta inhibitor has the potential to reduce the dose and consequently the toxic side-effects of doxorubicin, and improve its efficacy in the inhibition of breast cancer growth and metastasis.
最近的研究表明，上皮-间质转化（EMT）的诱导可能赋予乳腺癌细胞转移和自我更新的特性，导致耐药性和肿瘤复发。TGFβ是 EMT 的有效诱导剂，并已被证明在各种乳腺癌细胞和动物模型中促进肿瘤进展。
我们报告化疗药物多柔比星激活人源和鼠源乳腺癌细胞中的 TGFβ信号。多柔比星诱导 EMT，促进侵袭，并增强鼠源 4T1 乳腺癌细胞中具有干细胞表型的细胞生成，这些作用可被 TGFβ Ⅰ型受体激酶抑制剂（TβRI-KI）显著抑制。我们研究了 TβRI-KI 与多柔比星联合在转移性乳腺癌动物模型中的潜在协同抗肿瘤活性。与单独治疗相比，多柔比星与 TβRI-KI 的联合使用增强了多柔比星降低肿瘤生长和肺转移的疗效，在 4T1 原位异种移植模型中。单独使用多柔比星治疗会增强人源乳腺癌 MDA-MB-231 原位异种移植模型中的肺转移和 4T1 原位异种移植模型中的骨转移，而当 TβRI-KI 与多柔比星联合使用时，这些转移明显受到抑制。
这些观察结果表明，化疗药物在癌细胞中对 TGFβ 通路的不利激活以及肿瘤微环境中 TGFβ 水平的升高可能导致 EMT 和癌症干细胞的产生，从而导致对化疗的耐药性。我们的结果表明，多柔比星与 TGFβ 抑制剂的联合治疗有可能降低多柔比星的剂量，从而降低其毒性副作用，并提高其抑制乳腺癌生长和转移的疗效。
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