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  • Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression.

Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression.

Developmental cell (2020-02-23)
Timothy Marsh, Candia M Kenific, Deepthisri Suresh, Hugo Gonzalez, Eliah R Shamir, Wenbin Mei, Alexandra Tankka, Andrew M Leidal, Sandhya Kalavacherla, Kimberly Woo, Zena Werb, Jayanta Debnath
要旨

Although autophagy is being pursued as a therapeutic target in clinical oncology trials, its effects on metastasis, the principal cause of cancer mortality, remain unclear. Here, we utilize mammary cancer models to temporally delete essential autophagy regulators during carcinoma progression. Though genetic ablation of autophagy strongly attenuates primary mammary tumor growth, impaired autophagy promotes spontaneous metastasis and enables the outgrowth of disseminated tumor cells into overt macro-metastases. Transcriptomic analysis reveals that autophagy deficiency elicits a subpopulation of otherwise luminal tumor cells exhibiting basal differentiation traits, which is reversed upon preventing accumulation of the autophagy cargo receptor, Neighbor to BRCA1 (NBR1). Furthermore, pharmacological and genetic induction of autophagy suppresses pro-metastatic differentiation and metastatic outgrowth. Analysis of human breast cancer data reveal that autophagy gene expression inversely correlates with pro-metastatic differentiation signatures and predicts overall and distant metastasis-free survival. Overall, these findings highlight autophagy-dependent control of NBR1 as a key determinant of metastatic progression.

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Sigma-Aldrich
タモキシフェン, ≥99%
Sigma-Aldrich
モノクローナル抗FLAG® M2抗体 マウス宿主抗体, 1 mg/mL, clone M2, affinity isolated antibody, buffered aqueous solution (50% glycerol, 10 mM sodium phosphate, and 150 mM NaCl, pH 7.4)
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(Z)-4-ヒドロキシタモキシフェン, ≥98% Z isomer
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クロロキン 二リン酸塩, powder or crystals, 98.5-101.0% (EP)
Supelco
ラパマイシン, VETRANAL®, analytical standard
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Anti-Glyceraldehyde-3-Phosphate Dehydrogenase Antibody, clone 6C5, clone 6C5, Chemicon®, from mouse
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リボヌクレアーゼA ウシ膵臓由来, Type II-A, ≥60% (SDS-PAGE), >= 60 Kunitz units/mg protein
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Anti-LC3 Antibody, serum, from rabbit
Supelco
Injection Tee, size 6 in. (15 cm)