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The NAD+-dependent deacetylase Sirtuin 1 (SIRT1) is down-regulated in triple-negative breast cancer. To determine the mechanistic basis by which reduced SIRT1 expression influences processes related to certain aggressive cancers, we examined the consequences of depleting breast cancer cells of SIRT1. We discovered that reducing SIRT1 levels decreased the expression of one particular subunit of the vacuolar-type H+ ATPase (V-ATPase), which is responsible for proper lysosomal acidification and protein degradation. This impairment in lysosomal function caused a reduction in the number of multi-vesicular bodies (MVBs) targeted for lysosomal degradation and resulted in larger MVBs prior to their fusing with the plasma membrane to release their contents. Collectively, these findings help explain how reduced SIRT1 expression, by disrupting lysosomal function and generating a secretome comprising exosomes with unique cargo and soluble hydrolases that degrade the extracellular matrix, can promote processes that increase breast-cancer-cell survival and invasion. • SIRT1 expression is frequently decreased in aggressive breast cancers • Reducing SIRT1 levels in breast cancer cells impairs lysosomal acidification • Loss of SIRT1 gives rise to a secretome that promotes cell invasion and survival • SIRT1 mediates these effects by regulating V-ATPase expression Sirtuin 1 (SIRT1) expression is down-regulated in triple-negative breast cancer. Latifkar et al. show how reducing SIRT1 levels inhibit proper lysosomal function and, in doing so, results in the generation of a secretome with unique components, i.e., exosomes and resident lysosomal hydrolases, that promote the aggressiveness of breast cancer cells. [ABSTRACT FROM AUTHOR]