Predictive and prognostic value of ZEB1 protein expression in breast cancer patients with neoadjuvant chemotherapy

Abstract

Background Zinc finger E-box binding homeobox 1 (ZEB1) is a molecule involved in the progression of epithelial-to-mesenchymal transition (EMT) in various kinds of cancers. Here, we aimed to determine whether the expression of the ZEB1 protein is related to the response of patients to neoadjuvant therapy as well as their survival outcome. Methods Immunohistochemistry (IHC) was performed on paraffin-embedded tumor samples from core needle biopsy before neoadjuvant therapy (NAT). Univariate and multivariate logistic regression analyses were used to analyze the associations between the protein expression of ZEB1 and the pathological complete response (pCR) outcome. Kaplan–Meier plots and log-rank tests were used to compare disease-free survival (DFS) between groups. A Cox proportional hazards model was used to calculate the adjusted hazard ratio (HR) with a 95% confidential interval (95% CI). Results A total of 75 patients were included in the IHC test. High ZEB1 protein expression was associated with a low pCR rate in both univariate (OR = 0.260, 95% CI 0.082–0.829, p = 0.023) and multivariate (OR = 0.074, 95% CI 0.011–0.475, p = 0.006) logistic regression analyses. High ZEB1 protein expression was also associated with a short DFS according to both the log-rank test ( p = 0.023) and Cox proportional hazard model (HR = 9.025, 95% CI 1.024–79.519, p = 0.048). In hormone receptor positive (HorR-positive) patients, high ZEB1 protein expression was also associated with a lower pCR (OR = 0.054, 95% CI 0.007–0.422, p = 0.005) and a poorer DFS (HR = 10.516, 95% CI 1.171–94.435, p = 0.036) compared with low ZEB1 protein expression. In HER2-overexpressing patients, ZEB1 protein expression was also associated with poor survival ( p = 0.042). Conclusions Our results showed that high ZEB1 protein expression was a negative predictive marker of pCR and DFS in neoadjuvant therapy in breast cancer patients and in HorR-positive and HER2-overexpressing subgroups. Trial registration NCT, NCT02199418. Registered 24 July 2014—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02199418?term=NCT02199418&rank=1 . NCT, NCT 02221999. Registered 21 August 2014—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02221999?term=NCT02221999&rank=1

Breast cancer pathogenesis is linked to the intra-tumoral estrogen sulfotransferase (hSULT1E1) expressions regulated by cellular redox dependent Nrf-2/NFκβ interplay

“…A transcription regulator ZEB1 targets E-cadherin repression which is a prerequisite for EMT state. So, it is noteworthy that the EMT status linked to ZEB1 expression does not only indicate the mechanistic steps of disease pathogenesis but also it could be a potential therapeutic target [90,91]. Moreover, ZEB1 protein expression has some predictive outcome during neoadjuvant therapy in breast cancer patients.…”

“…Proper staging is critical for determining the appropriate clinical treatment course and surgical planning. Neoadjuvant therapies, where patients receive systemic therapy before surgical removal of the tumor, can downstage tumors allowing breast-conserving surgery, rather than mastectomy [91,95]. The effectiveness of standard and/or potential new therapies can be tested in the neoadjuvant pre-surgical setting [91].…”

“…Neoadjuvant therapies, where patients receive systemic therapy before surgical removal of the tumor, can downstage tumors allowing breast-conserving surgery, rather than mastectomy [91,95]. The effectiveness of standard and/or potential new therapies can be tested in the neoadjuvant pre-surgical setting [91]. It can potentially help to identify markers differentiating patients that will potentially benefit from continuing with the same or a different adjuvant treatment enabling personalised treatment [95].…”

Up-regulated Linc00472 suppresses development of lung cancer cell via inhibition of MiR-196b-5p

“…Vimentin has been considered to be an EMT marker that is ubiquitously expressed in normal mesenchymal cells and exerts its effect to maintain cellular integrity [35]. ZEB1 is zinc finger E-box binding homeobox 1 that involved in the progression of EMT in various kinds of cancers [36]. Furthermore, the EMT process was described by lacking cell-cell adhesion, which has an association of migratory and invasive features [37].…”

PKCα Modulates Epithelial-to-Mesenchymal Transition and Invasiveness of Breast Cancer Cells Through ZEB1

“…Several studies showed that ZEB1 (Zinc Finger E-box Binding Homeobox 1) has an active role in the induction of EMT in diverse epithelial malignancies, such as colon, prostate, pancreas, lung and breast cancer (10–15). Notably, the expression of ZEB1 in these tumors correlates with the loss of E-cadherin and is associated with advanced or metastatic disease, by triggering combined activation of cell motility and stemness properties (10, 16–18).…”