# Frizzled‐9 Expression Is Associated With Aggressive Clinicopathological Features and Reduced Overall Survival in Invasive Breast Carcinoma

## TL;DR

Frizzled-9 (FZD9) is linked to aggressive breast cancer features and worse survival, suggesting it could be a marker for tumor aggressiveness and treatment response.

## Contribution

This study identifies FZD9 as a potential biomarker for aggressive breast cancer and shows its dynamic regulation by therapies.

## Key findings

- FZD9 expression is more common in HER2-enriched tumors and those with high Ki-67 and advanced T-stage.
- FZD9-positive tumors correlate with reduced overall survival.
- FZD9 transcriptional responses to treatments vary widely depending on the tumor's molecular background.

## Abstract

The Wnt/Frizzled signaling pathway is implicated in tumor progression, yet the expression patterns and regulatory dynamics of Frizzled class receptor 9 (FZD9) in breast cancer remain poorly defined. This study evaluated FZD9 protein expression in breast tumors and explored its transcriptional modulation in breast cancer cell lines exposed to cytotoxic and epigenetic agents. Immunohistochemical analysis was performed in 81 breast cancer cases representing major molecular subtypes. In parallel, breast cancer cell lines were treated with trichostatin A, 5‐aza‐2′‐deoxycytidine, cisplatin, doxorubicin, paclitaxel, and ionizing radiation, followed by quantification of FZD9 mRNA levels by RT‐qPCR. FZD9 protein expression was more frequent in HER2‐enriched tumors, cases with high Ki‐67 index, and advanced T‐stage. FZD9‐positive tumors were associated with reduced overall survival, whereas relapse‐free survival showed no significant difference. Baseline FZD9 transcript levels varied substantially across cell lines, and transcriptional responses to chemotherapy, radiation, and epigenetic treatment were highly context‐dependent, with divergent patterns observed according to molecular background. Collectively, these findings indicate that FZD9 expression in breast cancer is heterogeneous, associated with aggressive clinicopathological features, and dynamically modulated by therapeutic exposures, supporting its consideration as an exploratory marker of tumor aggressiveness and therapy‐related biological responses.

Graphical summary illustrating the evaluation of FZD9 in breast cancer. FZD9 protein expression was assessed by immunohistochemistry in 81 breast tumor samples and further investigated in breast cancer cell lines exposed to cytotoxic and epigenetic treatments. Higher FZD9 expression was associated with aggressive clinicopathological features and poorer overall survival. Experimental assays demonstrated heterogeneous transcriptional responses to therapeutic agents, underscoring the context‐dependent role of FZD9 in breast cancer biology. FZD9, Frizzled‐9; Wnt, Wingless‐related integration site; IHC, immunohistochemistry; TSA, trichostatin A; 5AZA, 5‐aza‐2’‐deoxycytidine.