Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells.

Malignant breast tissue contains a rare population of multi-potent cells with the capacity to self-renew; these cells are known as cancer stem-like cells (CSCs) or tumor-initiating cells. Primitive mammary CSCs/progenitor cells can be propagated in culture as floating spherical colonies termed ‘mammospheres'. We show here that the expression of the autophagy protein Beclin 1 is higher in mammospheres established from human breast cancers or breast cancer cell lines (MCF-7 and BT474) than in the parental adherent cells. As a result, autophagic flux is more robust in mammospheres. We observed that basal and starvation-induced autophagy flux is also higher in aldehyde dehydrogenase 1-positive (ALDH1+) population derived from mammospheres than in the bulk population. Beclin 1 is critical for CSC maintenance and tumor development in nude mice, whereas its expression limits the development of tumors not enriched with breast CSCs/progenitor cells. We found that decreased survival in autophagy-deficient cells (MCF-7 Atg7 knockdown cells) during detachment does not contribute to an ultimate deficiency in mammosphere formation. This study demonstrates that a prosurvival autophagic pathway is critical for CSC maintenance, and that Beclin 1 plays a dual role in tumor development.

恶性乳腺组织包含一小部分具有自我更新能力的多能细胞；这些细胞被称为癌干细胞样细胞（CSCs）或肿瘤起始细胞。原始乳腺CSCs/祖细胞可以在培养中作为被称为“乳腺球”的漂浮球形集落进行增殖。我们在此表明，自噬蛋白Beclin 1在从人乳腺癌或乳腺癌细胞系（MCF - 7和BT474）建立的乳腺球中的表达高于亲代贴壁细胞。因此，自噬通量在乳腺球中更强。我们观察到，在源自乳腺球的乙醛脱氢酶1阳性（ALDH1+）群体中，基础和饥饿诱导的自噬通量也高于总体群体。Beclin 1对裸鼠中CSC的维持和肿瘤发展至关重要，而其表达限制了未富集乳腺CSCs/祖细胞的肿瘤的发展。我们发现，自噬缺陷细胞（MCF - 7 Atg7敲低细胞）在脱离过程中存活率降低并不导致乳腺球形成的最终缺陷。这项研究表明，一种促存活的自噬途径对CSC的维持至关重要，并且Beclin 1在肿瘤发展中起双重作用。