Qadir M A, Kwok B, Dragowska W H, To K H, Le D, Bally M B, Gorski Sharon M
Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada.
Breast Cancer Res Treat. 2008 Dec;112(3):389-403. doi: 10.1007/s10549-007-9873-4. Epub 2008 Jan 3.
Macroautophagy (autophagy), a process for lysosomal degradation of organelles and long-lived proteins, has been linked to various pathologies including cancer and to the cellular response to anticancer therapies. In the human estrogen receptor positive MCF7 breast adenocarcinoma cell line, treatment with the endocrine therapeutic tamoxifen was shown previously to induce cell cycle arrest, cell death, and autophagy. To investigate specifically the role of autophagy in tamoxifen treated breast cancer cell lines, we used a siRNA approach, targeting three different autophagy genes, Atg5, Beclin-1, and Atg7. We found that knockdown of autophagy, in combination with tamoxifen in MCF7 cells, results in decreased cell viability concomitant with increased mitochondrial-mediated apoptosis. The combination of autophagy knockdown and tamoxifen treatment similarly resulted in reduced cell viability in the breast cancer cell lines, estrogen receptor positive T-47D and tamoxifen-resistant MCF7-HER2. Together, these results indicate that autophagy has a primary pro-survival role following tamoxifen treatment, and suggest that autophagy knockdown may be useful in a combination therapy setting to sensitize breast cancer cells, including tamoxifen-resistant breast cancer cells, to tamoxifen therapy.
巨自噬（自噬）是一种细胞器和长寿蛋白的溶酶体降解过程，与包括癌症在内的多种病理状况以及细胞对抗癌疗法的反应有关。在人雌激素受体阳性MCF7乳腺腺癌细胞系中，先前已证明用内分泌治疗药物他莫昔芬处理可诱导细胞周期停滞、细胞死亡和自噬。为了具体研究自噬在他莫昔芬处理的乳腺癌细胞系中的作用，我们采用了小干扰RNA（siRNA）方法，靶向三种不同的自噬基因，即自噬相关基因5（Atg5）、Beclin-1和自噬相关基因7（Atg7）。我们发现，在MCF7细胞中，自噬基因敲低与他莫昔芬联合使用会导致细胞活力下降，同时线粒体介导的凋亡增加。自噬基因敲低与他莫昔芬处理的联合同样导致雌激素受体阳性T-47D和他莫昔芬耐药的MCF7-HER2乳腺癌细胞系的细胞活力降低。总之，这些结果表明自噬在他莫昔芬处理后具有主要的促生存作用，并表明自噬基因敲低可能在联合治疗中有用，以使乳腺癌细胞，包括他莫昔芬耐药的乳腺癌细胞，对他莫昔芬治疗敏感。
