Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers

Abstract

The triple-negative breast cancer (TN BC) subtype is the most aggressive form of invasive BC. Despite intensive efforts to improve BC treatments, patients with TN BC continue to exhibit poor survival, with half developing resistance to chemotherapy. Here we identify autophagy as a key mechanism in the progression and chemoresistance of a subset of TN tumors. We demonstrate that LC3B, a protein involved in autophagosome formation, is a reliable marker of poor prognosis in TN BC, validating this prognostic value at both the mRNA and protein levels in several independent cohorts. We also show that LC3B has no prognostic value for other BC subtypes (Luminal or HER2 BC), thus revealing a specific impact of autophagy on TN tumors. Autophagy is essential for the proliferative and invasive properties in 3D of TN BC cells characterized by high LC3B levels. Interestingly, the activity of the transcriptional co-activator YAP1 (Yes-associated protein 1) is regulated by the autophagy process and we identify YAP1 as a new actor in the autophagy-dependent proliferative and invasive properties of high-LC3B TN BC. Finally, inhibiting autophagy by silencing ATG5 or ATG7 significantly impaired high-LC3B TN tumor growth in vivo. Moreover, using a patient-derived TN tumor transplanted into mice, we show that an autophagy inhibitor, chloroquine, potentiates the effects of chemotherapeutic agents. Overall, our data identify LC3B as a new prognostic marker for TN BC and the inhibition of autophagy as a promising therapeutic strategy for TN BC patients.

Morphometric analysis of a triple negative breast cancer cell line in hydrogel and monolayer culture environments

“…For example, in cancer, autophagy can act as a tumor suppressor during the initial stages of tumor progression, but may promote tumor cell survival in later stages (Tu et al, 2011; Mah & Ryan, 2012; Kaminskyy et al, 2012; Huang et al, 2014; Morgan et al, 2014; Galluzzi et al, 2015). Lefort et al (2014) have shown that autophagy-linked genes are upregulated in TNBC cell lines, including the HCC70 cell line that was used in the current study, cultured in a laminin-rich extracellular matrix (Lefort et al, 2014). Moreover, TNBC cell lines, including HCC70, appear to respond to the suppression of the NEET family proteins, mitoNEET (mNT) and Nutrient-deprivation autophagy factor-1 (NAF-1), with impaired ultrastructural mitochondrial morphology and autophagosome accumulation (Sohn et al, 2013).…”

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling

“…At present, autophagy has become a potential anticancer target both in cancer prevention and therapy, despite its controversial functions including OSCC [13,14,15,16,17]. Reactive oxygen species (ROS) can lead to various effects on different signaling pathways and results in genomic instability by inducing DNA damage.…”

Autophagy Induced during Pancreatitis Promotes KRAS-Dependent Transformation in the Pancreas

“…Although the mechanism by which autophagy induces cell death is not yet clearly established, it appears to be mediated by the activation of caspase 3 (36). Therefore, in line with such knowledge, co-treatment with chloroquine appears to enhance the effect of many anticancer drugs in vitro as well as in some preclinical models (37–41), although a clinical study has yet to confirm its benefit as a co-treatment.…”