The significance of the Ferroptosis Markers (SLC7A11, ACSL4) and Their Relation to M6A Modification Regulators (HNRNPA2B1, YTHDF1) in Breast Invasive Ductal Carcinoma

Background: Ferroptosis which is a unique type of regulated cell death, has been featured as an urgent mechanism in development and progression of cancer, especially regarding the resistance to chemotherapy.
Subjects and methods: This retrospective study involved immunohistochemical analysis of SLC7A11, ACSL4, HNRNPA2B1, and YTHDF1 expression in 95 cases of invasive ductal carcinoma of the breast, all had been treated with neoadjuvant chemotherapy.
Results: Positive expression of SLC7A11 was identified in 63.2% of cases and demonstrated a statistically significant linear association with tumor grade, clinical tumor stage, clinical lymph node (LN) stage, postoperative pathological tumor and nodal staging and molecular subtypes. High expression of ACSL4 was observed in 51.6% of cases and demonstrated a statistically significant inverse relationship with tumor grade, clinical tumor staging, clinical lymph node (LN) staging, and postoperative pathological tumor and nodal staging. Positive HNRNPA2B1 expression was apparent in 64.2% of cases and exhibited a statistically significant relationship with tumor grade, clinical tumor staging, clinical LN staging, pathological tumor and nodal staging (postoperative) and molecular type. High expression of YTHDF1 was apparent in 62.1% of cases and exhibited statistically significant relationship with tumor grade, clinical tumor staging, clinical LN staging, pathological tumor and nodal staging. Pathological complete response (pCR) was significantly frequent in cases with early clinical tumor and nodal stage, negative SLC7A11 expression (ferroptosis inhibitor), high ACSL4 level (ferroptosis inducer), negative HNRNPA2B1 and low YTHDF1 expression.
Conclusion: The expression of ferroptosis regulators SLC7A11 and ACSL4 significantly impacted the therapeutic response to neoadjuvant chemotherapy suggesting their value as predictive markers and promising therapeutic targets for breast ductal carcinoma. Furthermore, the m6A modifications of ferroptosis regulators SLC7A11 and ACSL4, mediated by HNRNPA2B1 and YTHDF1, may serve as a mechanism for inducing ferroptosis in breast cancer.