NPC1 Confers Metabolic Flexibility in Triple Negative Breast Cancer

Abstract

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.

MicroRNA Profile, Putative Diagnostic Biomarkers and RNA-Based Therapies in the Inherited Lipid Storage Disease Niemann-Pick Type C

“…Consistently, its silencing led to decelerated proliferation and decreased invasiveness, altered mitochondrial function and morphology, suppression of mTOR signaling and accumulation of autophagossomes [86]. Additionally, the NPC1 gene has also been shown to be highly expressed and directly targeted by miR-200c in aggressive breast cancer [86].…”

“…Additionally, the NPC1 gene has also been shown to be highly expressed and directly targeted by miR-200c in aggressive breast cancer [86].…”

“…In order to unveil the genes affected by miR-200c, it was observed that the restoration of miR-200c to cancer cells reduces the levels of certain immune modulatory response genes and among them, NPC1 was found [85]. Consistently, its silencing led to decelerated proliferation and decreased invasiveness, altered mitochondrial function and morphology, suppression of mTOR signaling and accumulation of autophagossomes [86]. Additionally, the NPC1 gene has also been shown to be highly expressed and directly targeted by miR-200c in aggressive breast cancer [86].…”

Host cellular factors involved in pseudorabies virus attachment and entry: a mini review

“…NPC1 belongs to the cholesterol family that is essential for the lysosomal cholesterol transport from late endosomes to cellular membrane ( 31 ). Abnormal expression of NPC1 is associated with various cancers ( 32 , 33 ). Recently, the contribution of NPC1 to virus infection has garnered attention, and the NPC1-specific inhibitor, U18666A, has been widely used to explore the potential roles of NPC1 in viral infection ( 34 ).…”

Focusing on the Abnormal Events of NPC1, NPC2, and NPC1L1 in Pan-Cancer and Further Constructing LUAD and KICH Prediction Models

“…The NPCs are NPC1, NPC2, and NPC1L1. NPCs’ main biological activity is cholesterol transfer. − Cholesterol has recently been discovered to have a major influence on the course of most malignancies. , NPC1 deficiency is linked to the development of several malignancies, including Niemann–Pick disease, breast cancer, and can also increase phagocyte absorption and impede lipid transport by microglia . NPC2 mutations have been linked to thyroid cancer, glioma, hepatocellular carcinoma, and nasopharyngeal carcinoma .…”