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

Abstract

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.

IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway

“…Remarkably, the prosurvival functions of NFKB pathway and autophagy have both been implicated in the adhesion-independent growth and anoikis resistance of tumor cells. 38,[42][43][44][45] Because anoikis resistance is associated with cancer progression and metastasis, in future work, it will be important to further scrutinize whether IKK critically regulates detachment-induced autophagy in cancer cells as well as to ascertain if IKK inhibition can be exploited to inhibit cancer cell survival in foreign tissue environments.…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…Low levels of autophagic activity are observed under physiological conditions, while in tumor cells, autophagy promotes cell survival during the frequent nutrient restriction and hypoxia [49]. Autophagy was found to sustain the maintenance of cancer stem cell phenotype, and cooperates to chemo-and radio-resistance [50][51][52][53]. Inhibition of autophagy, on the contrary, increases chemo-and radio-sensitivity [54].…”

Autophagy in colorectal cancer: An important switch from physiology to pathology

“…KRasG12Ddriven pancreatic adenocarcinoma cells that enter a state of dormancy in response to oncogene ablation have recently been shown to activate autophagy to efficiently counteract metabolic stress [62] , demonstrating the functional and phenotypic features of cancer stem cells. In addition, mammary cancer stem cells are often characterized by elevated autophagic flux, and their ability to efficiently form tumors in vivo appears to rely on autophagy, as tumor formation can be abolished through the genetic inhibition of BECN1 or ATG4A [63,64] . Thus, autophagy may also sustain tumor progression by preserving the viability of the cancer stem cell compartment and/or by promoting the persistence of dormant cancer cells.…”