NPC1 Confers Metabolic Flexibility in Triple Negative Breast Cancer

Simple Summary Triple negative breast cancer is an aggressive breast cancer subtype with limited targeted therapeutic options. As a method of identifying novel therapeutic targets in this disease subtype, we utilize a microRNA that reverses the Epithelial-to-Mesenchymal Transition, which reveals Niemann-Pick C1 (NPC1) as a gene highly expressed in triple negative breast cancer. Silencing of NPC1 causes significant loss of tumor-promoting capabilities of these cell lines. We find that NPC1 promotes cell proliferation in soft agar and invasive capacity, while silencing impairs these functions and leads to mitochondrial dysfunction and suppression of pro-tumorigenic signaling. This work suggests NPC1 as a potential target and a mediator of breast cancer aggression. Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal cholesterol transporter Niemann-Pick type C1 is highly expressed in TNBC as compared to estrogen receptor-positive (ER+) breast cancer, and is significantly elevated in high-grade disease. We demonstrated that NPC1 is directly targeted by microRNA-200c (miR-200c), a potent suppressor of EMT, providing a mechanism for its differential expression in breast cancer subtypes. The silencing of NPC1 in TNBC causes an accumulation of cholesterol-filled lysosomes, and drives decreased growth in soft agar and invasive capacity. Conversely, overexpression of NPC1 in an ER+ cell line increases invasion and growth in soft agar. We further identified TNBC cell lines as cholesterol auxotrophs, however, they do not solely depend on NPC1 for adequate cholesterol supply. The silencing of NPC1 in TNBC cell lines led to altered mitochondrial function and morphology, suppression of mTOR signaling, and accumulation of autophagosomes. A small molecule inhibitor of NPC1, U18666A, decreased TNBC proliferation and synergized with the chemotherapeutic drug, paclitaxel. This work suggests that NPC1 promotes aggressive characteristics in TNBC, and identifies NPC1 as a potential therapeutic target.

Automated summary

This study identifies NPC1 as a highly expressed gene in triple negative breast cancer, and silencing NPC1 inhibits tumor-promoting capabilities. The findings suggest NPC1 as a potential therapeutic target and a mediator of breast cancer aggression.