Immunohistochemical Expression of NRF2 and KEAP1 in Primary Invasive Breast Carcinoma: Relations to Molecular Subtypes and Available Clinicopathological Parameters

Background: Breast carcinoma (BC) shows various molecular alterations with several complex interacting factors. One of the most frequently described mutations in BC is NRF2, also known as nuclear factor erythroid 2-related factor 2, which is thought to act as an oncogene or a tumor suppressor gene. NRF2 is normally bound to its repressor Kelch-like ECH-associated protein 1 (KEAP1). Oxidative stress induces KEAP1 conformational changes that inhibit NRF2 degradation, allowing NRF2 to enter the nucleus and encouraging its expression. Aim: To assess the immunohistochemical staining of NRF2 and KEAP1, and their relations to molecular subtypes and different clinicopathological parameters in BC. Materials and Methods: This study was conducted using a retrospective cross-sectional design on 80 cases, primarily diagnosed as BC were exposed to routine H&E, along with immunohistochemical staining using NRF2 and KEAP1 antibodies. Results: The nucleus of malignant cells expressed NRF2. High nuclear expression was significantly related to higher tumor grade (p ≤ 0.05) and advanced tumor stage (p ≤0.05), and the molecular subtype (p ≤0.05). The cytoplasm of malignant cells expressed KEAP1. Higher cytoplasmic staining was significantly associated with diminished tumor grade (p ≤0.05), early tumor stage (p ≤0.05), and luminal molecular genotype (p ≤0.05). A significant inverse relation between NRF2 and KEAP1 expressions were detected (p ≤0.05). Conclusions: High NRF2 and low KEAP1 immunohistochemical expression exhibited a significant relation with adverse clinicopathological parameters and were associated with aggressive tumor behavior.