Expression of Autophagy and Mitophagy Markers in Breast Cancer Tissues

Abstract

Mitochondria play important roles in regulating cell bioenergetics status and reactive oxygen species (ROS) generation. ROS-induced mitochondrial damage is among the main intracellular signal inducers of autophagy. Autophagy is a cellular catabolic process that regulates protein and organelle turnover, while a selective form of autophagy, mitophagy, specifically targets dysfunctional mitochondrial degradation. This study aims to measure the levels of autophagy, mitophagy, oxidative stress, and apoptosis in invasive breast carcinoma tissues using immunohistochemistry (IHC). Tissue microarrays of 76 patients with breast cancer were stained with six IHC markers (MnSOD, Beclin-1, LC3, BNIP3, Parkin, and cleaved caspase 3). The expression intensity was determined for each tumor tissue and the adjacent tumor-matched control tissues. Intermediate and strong staining scores of MnSOD, Beclin-1, LC-3, BNIP-3, and Parkin were significantly higher in tumor tissues compared to the adjacent matched control. The scoring intensity was further classified into tissues with negative staining and positive staining, which showed that positive scores of Beclin-1 and Parkin were significantly high in tumor tissues compared to other markers. Positive association was also noted between BNIP-3 and Beclin-1 as well as LC-3 and cleaved caspase-3 immunostaining. To our knowledge, this is one of the first studies that measure both mitophagy and autophagy in the same breast cancer tissues and the adjacent matched control. The findings from this study will be of great potential in identifying new cancer biomarkers and inspire significant interest in applying anti-autophagy therapies as a possible treatment for breast cancer.

Characterization of Mitochondrial Proteome and Function in Luminal A and Basal-like Breast Cancer Subtypes Reveals Alteration in Mitochondrial Dynamics and Bioenergetics Relevant to Their Diagnosis

“…In addition to decreased mitochondrial function, we show that activation of mitophagy is a response to the decreased mitochondrial membrane potential (Figure 4A,B). Consistent with our results, previous research has reported that high LC3, PINK1 and p62 protein levels are associated with triple-negative BC (TNBC) patients and with poor response to chemotherapy, similar results have also been found in colorectal cancer, gastric, malignant melanoma, and esophageal cancer [54][55][56][57][58][59][60][61]. This demonstrates that deficiency of mitochondrial activity correlates with the invasiveness and metastatic capacity of the basal-like subtype of BC [62].…”

TFEB, SIRT1, CARM1, Beclin-1 expression and PITX2 methylation in breast cancer chemoresistance: a retrospective study

“…Previous studies demonstrate that TFEB and CARM1 act as effectors of the autophagy process, and their significant correlation in our results confirms this [15]. Besides, SIRT1, CARM1, and TFEB positively correlated with Beclin-1, a known marker of the autophagy process [21]. Even by selecting only the luminal molecular subtypes, it emerges that the rho coefficient of the correlation between TFEB and CARM1 approaches significance (Supplemental Table 2).…”

“…SIRT1 is known to be a significant prognostic factor in many cancers [18], and a high SIRT1 expression is known to be an unfavorable prognostic factor in breast cancer [19,20]. In addition, Beclin-1 is a known marker of autophagy [21,22].…”

Anticancer and Anti-Inflammatory Mechanisms of NOSH-Aspirin and Its Biological Effects

“…It is currently assumed that ROS plays a dual role in malignancies. On the one hand, ROS can activate a variety of redox reactions and signaling pathways, such as the MAPK pathway, PI3K/AKT pathway, NF-κB pathway, and Keap1-Nrf2-ARE pathway, to promote tumor occurrence, development, and metastasis; on the other hand, when ROS exists in excess, it can cause cellular stress and damage through oxidative stress mechanism and eventually lead to cell death [62][63][64]. It all depends on the severity of the ROS excess and the duration of exposure; oxidative stress can activate cell survival or apoptosis mechanisms.…”