A study of the role of androgen receptor and androgen receptor variant 7 in TNBC patients and the effect of their targeting by Enzalutamide and EPI-001 in MDA-MB-231

Belal M Ali; Hanan S El-Abhar; Ghada Mohamed; Hanan R Nassar; Nelly Aliedin; Marwa Sharaky; Samia A Shouman; Marwa Kamel

doi:10.1016/j.jsbmb.2024.106636

A study of the role of androgen receptor and androgen receptor variant 7 in TNBC patients and the effect of their targeting by Enzalutamide and EPI-001 in MDA-MB-231

J Steroid Biochem Mol Biol. 2024 Nov 12:245:106636. doi: 10.1016/j.jsbmb.2024.106636. Online ahead of print.

Authors

Belal M Ali¹, Hanan S El-Abhar², Ghada Mohamed³, Hanan R Nassar⁴, Nelly Aliedin⁵, Marwa Sharaky⁶, Samia A Shouman⁷, Marwa Kamel⁸

Affiliations

¹ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Ministry of Health and Population, Egypt. Electronic address: belal.m.ali1987@gmail.com.
² Department of Pharmacology, Toxicology, and Biochemistry, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo, Egypt. Electronic address: Hanan.elabhar@fue.edu.eg.
³ Department of Pathology, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: Dr.ghada.elshafaee@gmail.com.
⁴ Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: nhanan_67@yahoo.com.
⁵ Department of Medical Statistics Department, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: nelly26660@gmail.com.
⁶ Department of Cancer Biology, Unit of Pharmacology and Experimental Therapeutics, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: marwa.sharaky@nci.cu.edu.eg.
⁷ Department of Cancer Biology, Unit of Pharmacology and Experimental Therapeutics, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: samia.shouman@nci.cu.edu.eg.
⁸ Department of Cancer Biology, Unit of Pharmacology and Experimental Therapeutics, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: marwawka@cu.edu.eg.

PMID: 39536950
DOI: 10.1016/j.jsbmb.2024.106636

Abstract

The lack of targeted therapy for triple-negative breast cancer (TNBC) is among the mainsprings of its poor prognosis. This study aimed to elucidate the role of the androgen receptor (AR) and its splice variant 7 (ARv7) in TNBC patients. Further, the molecular impact of their blockers, Enzalutamide and EPI-001, on the TNBC cell line MDA-MB-231 was investigated. Thereby, immunohistochemical expression of AR/ARv7 was assessed for TNBC Egyptian patients. Moreover, bioinformatics analysis of AR/ARv7 RNA status was carried out on TNBC patients from The Cancer Genome Atlas Breast Carcinoma project (TCGA-BRCA). Data from both groups was correlated with patients' clinicopathological features. Besides, scratch wound healing assay and ELISA were employed to assess the effect of AR/ARv7 blockers on several metastasis markers in MDA-MB-231 cell line. In the Egyptian-TNBC patients, AR expression was associated with worse 7-year DFS (40.6 ± 18.6 %). In addition, ARv7 showed cytoplasmic and nuclear patterns, and both cytoplasmic and nuclear ARv7⁺ patients demonstrated a worse 7-year DFS (22.7 ± 17.7 % and 20 ± 17.9 %) and overall survival (63.6 ± 14.5 % and 40 ± 21.8 %). Importantly, 80 % of the nuclear ARv7⁺ patients developed distant metastasis. The data of the TCGA-TNBC patients showed a tendency for poor outcomes in the high ARv7-expressing patients. Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis.

Keywords: Androgen receptor; Androgen receptor splice variant 7; EPI-001; Enzalutamide; Metastasis; Triple-negative breast cancer.