# Comprehensive Transcriptomic Analysis and Biomarker Prioritization of Hydroxyprogesterone in Breast Cancer

## TL;DR

This study explores how hydroxyprogesterone affects breast cancer at the molecular level and identifies potential biomarkers for further research.

## Contribution

The study identifies novel candidate biomarkers (FKBP5, CLDN4) and molecular pathways influenced by hydroxyprogesterone in breast cancer.

## Key findings

- HP exposure activates steroid-hormone and lipid/xenobiotic metabolism pathways in normal adjacent tissue.
- Tumor tissue shows significant tight-junction and ECM remodeling, with CLDN4 upregulation.
- FKBP5 and CLDN4 are prioritized as key biomarkers for HP's effects in breast cancer.

## Abstract

Hydroxyprogesterone (HP) is a synthetic progestogen widely used in obstetric care, and its potential influence on breast cancer biology has become an emerging area of interest. Despite its clinical use, the molecular mechanisms by which HP affects tumor tissue remain insufficiently explored. In this study, transcriptomic profiling was performed to investigate gene expression changes associated with HP in operable breast cancer. Pre-operative 17α-HP caproate (17-OHPC) exposure was associated, in normal adjacent tissue (NAT), with activation of steroid-hormone and lipid/xenobiotic-metabolism programs and crosstalk to phosphoinositide 3-kinase (PI3K)–Akt and nuclear factor kappa B (NF-κB). In NAT, these pathways showed the largest absolute log2 fold-change (|log2FC|); significance is reported as false discovery rate (FDR) throughout (e.g., FKBP5↑ with HP). In tumor tissue, the dominant signal reflected tight-junction/apical-junction and extracellular matrix (ECM)-receptor remodeling (e.g., CLDN4↑). We prioritized FKBP5 (HP pharmacodynamics) and CLDN4 (tumor baseline) as the main candidates; TSPO and SGK1 are reported as exploratory. This discovery-level, hypothesis-generating analysis nominates candidate biomarkers and pathway signals for prioritization and evaluation in independent datasets and future studies. These findings provide mechanistic insight into HP’s molecular effects in breast cancer and suggest potential applications in biomarker perioperative management.