Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity

Cicchini, Michelle; Chakrabarti, Rumela; Kongara, Sameera; Price, Sandy M.; Nahar, Ritu; Lozy, Fred; Vázquez, Alexei; Kang, Yibin; Karantza, Vassiliki

doi:10.4161/auto.34398

Cited by 130 publications

(129 citation statements)

References 61 publications

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“…This chronic state of tissue damage, cell death, and inflammation promotes compensatory proliferation, producing cells vulnerable to mutation and oncogenic transformation (White 2012). The situation may be similar in a mouse model of breast cancer in which allelic loss of becn1 promotes expansion of the stem cell pool susceptible to transformation by Wnt pathway activation (Cicchini et al 2014). However as mentioned above, this may be due to autophagy-independent mechanisms as well (Cicchini et al 2014).…”

Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

confidence: 99%

“…The situation may be similar in a mouse model of breast cancer in which allelic loss of becn1 promotes expansion of the stem cell pool susceptible to transformation by Wnt pathway activation (Cicchini et al 2014). However as mentioned above, this may be due to autophagy-independent mechanisms as well (Cicchini et al 2014).…”

Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

confidence: 99%

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Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

confidence: 99%

Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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“…Other distinguishing factors may exist such as differences in the level of expression of metadherin, which aids in the adhesion of cancer cells to the endothelium, and confers an enhanced chemoresistance to the cells [48]. Recent evidence also suggests that autophagy is a prosurvival trait held by CSCs, which may also allow them to travel through much smaller vessels [49][50][51][52].…”

Section: Intravasation Transport and Extravasationmentioning

confidence: 99%

Involvement of Mesenchymal Stem Cells in Cancer Progression and Metastases

Chang¹,

Schwertschkow²,

Nolta³

et al. 2015

CCDT

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Mesenchymal stem/stromal cells (MSCs) are known to be the helpers for the healing of tissue damage, often referred to as ambulatory cells. However, MSCs are also recruited by cancer cells to similarly aid in tumor growth and progression. In this review, some of the key steps in cancer progression and metastases are described including the various steps in which MSCs participate and may play important roles. MSCs aid in cancer cells' ability to evade immune attack, while promoting tumor angiogenesis, even being counter-acting against chemotherapeutics and other drugs used to fight various cancers. Furthermore, MSCs participate in many of the crucial steps in invasion and metastasis, including stimulating the epithelial-mesenchymal transition (EMT) and induction of stem-like properties that allow cancer stem cells to increase their survivability through the circulation. These steps are described in detail. Differences between circulating tumor cells (CTCs) and cancer stem cells (CSCs) are discussed, along with descriptions of the formation of a pre-metastatic niche, the role of exosomes from both cancer cells and MSCs in metastasis and tumor reseeding (self-seeding). More and more, MSCs are being proposed as a promising tumor targeting drug-delivery tool. In order to fulfill this promise, further understanding of the precise roles that MSCs play in the process of cancer metastases must be achieved, in attempting to create remedies that will improve the outcome of available therapeutics.

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“…3 Moreover, in mice, heterozygosity of Becn1, which induces a partial autophagy defect, 4 accelerates breast carcinogenesis in 2 different models, namely in multiparous FVB/N mice, as well as in cooperation with the transgenic expression of the Wnt1 oncogene. 5 High expression of the 2 autophagy-relevant proteins ATG5 and RB1CC1/FIP200 has a positive impact on breast cancer patient survival. 6 Although the absolute expression level of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 b) has no major impact on patient survival, 7 the absence of LC3B puncta, which correlates with increased levels of the autophagy receptor SQSTM1/p62 and hence indicates a reduction of autophagic flux, has a negative prognostic impact, as we have reported on 2 cohorts comprising approximately 1700 breast cancer patients who underwent adjuvant chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer

et al. 2016

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Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 b)-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8 C cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3 C regulatory T cells or CD68C tumor-associated macrophages), resulting in low CD8C ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8C cells and more FOXP3C or CD68 C cells, resulting in a major drop in the CD8 C :FOXP3 C or CD8 C :CD68 C ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3C and CD68 C cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.

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Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity

Cited by 130 publications

References 61 publications

Recent insights into the function of autophagy in cancer

Recent insights into the function of autophagy in cancer

Involvement of Mesenchymal Stem Cells in Cancer Progression and Metastases

The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer

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