DJ-1 protein expression as a predictor of pathological complete remission after neoadjuvant chemotherapy in breast cancer patients

Abstract

Parkinson's disease is associated with DJ-1/Parkinson protein 7 dysfunction. In contrast, hyperactivity of DJ-1 increases the resistance of cancer cells to apoptosis. Recent genetic studies showed that, in addition to apoptosis pathways, DJ-1 is also involved in cellular defense against reactive oxygen species. The activity of apoptotic and cellular defense pathways is key in determining drug sensitivity. DJ-1 overexpression is associated with various cancers. However, we previously found that there were approximately 50 % patients with breast cancers that expressed low levels of DJ-1 protein, despite mRNA upregulation. Furthermore, low DJ-1 expression was a significant predictor of poor clinical outcome in these patients. This study aimed to determine the association between low DJ-1 protein expression and pathological complete remission (pCR) after neoadjuvant chemotherapy in breast cancer patients. Expression of DJ-1 in pre-therapeutic needle biopsies and surgical specimens obtained from 205 breast cancer cases that received neoadjuvant chemotherapy was determined using immunohistochemistry and in situ hybridization. Chemotherapy comprised epirubicin/cyclophosphamide taxane-based regimens with or without the inclusion of trastuzumab. Univariate and multivariate analyses were used to evaluate the predictive value of DJ-1 on pCR. Low DJ-1 protein expression was detected in 45.3 % (93/205) of all breast cancer cases and in 79.6 % (39/49) of pCR cases, irrespective of maintained mRNA levels. DJ-1 expression [hazard ratio (HR): 1.36; 95 % confidence interval (CI): 1.01-1.84] and HER2 status (HR: 0.84; 95 % CI: 0.62-1.14), in contrast to histological grade, hormone receptors status, Ki-67 labeling index, and intrinsic subtype, were significant predictors of pCR. Low DJ-1 expression predicted pCR in luminal A (P = 0.0004), luminal B (P = 0.0194), and triple negative (P = 0.0143) subtypes breast cancer patients and in patients receiving additional trastuzumab treatment (P = 0.008). In conclusion, low DJ-1 protein expression is a significant predictor of pCR after neoadjuvant chemotherapy in breast cancer patients.

Preoperative serum 8-hydroxydeoxyguanosine is associated with chemoresistance and is a powerful prognostic factor in endometrioid-type epithelial ovarian cancer

“…In ovarian cancer, DJ-1 levels, measured by PCR from effusions, were more expressed at an advanced stage [ 38 ]. In gastric carcinoma DJ-1 plays an important role in the development of peritoneal carcinomatosis in vitro [ 39 ] and in breast cancer low DJ-1 immunohistochemical and FISH (fluorescence in situ hybridization) expression seems to predict pathological complete remission after neoadjuvant chemotherapy [ 40 ]. High DJ-1 immunohistochemical expression in pancreatic cancer is associated with chemoresistance [ 24 ].…”

Biological and Clinical Implications of Comorbidities in Parkinson’s Disease

“…Recently, PINK1 expression has been associated with poor response to chemotherapy (Yamashita et al, 2017 ). Mutations in DJ1 (PARK7, a regulator of the tumor suppressor PTEN) is observed in PD patients and in breast, lung, pancreatic, gastric and prostate cancers (Hod, 2004 ; He et al, 2011 ; Zeng et al, 2011 ; Kawate et al, 2013 ; Li et al, 2013 ). Another example, LRRK2 is overexpressed in papillary renal and thyroid carcinomas (Looyenga et al, 2011 ) and mutations in LRRK2 are associated with an increased risk for breast, non-skin and hematological cancers (Inzelberg et al, 2012 ; Ruiz-Martínez et al, 2014 ; Agalliu et al, 2015 ).…”

Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells

“…Table 1 showed significant upregulation of oxidative stress regulators sulfiredoxin, PDZ and LIM domain protein 1, while peroxiredoxins and DJ-1 (PARK7) proteins known to lessen oxidative damage, were downregulated. Studies demonstrate that these two proteins act as protective mediators to prevent ROS-induced apoptosis[42, 43]. Imbalances between ROS and antioxidant molecules, however, result in oxidative stress.…”