AKR1C2 Promotes Metastasis and Regulates the Molecular Features of Luminal Androgen Receptor Subtype in Triple Negative Breast Cancer Cells

Songbin Li; Woochan Lee; Woohang Heo; Hye-Youn Son; Yujeong Her; Jong-Il Kim; Hyeong-Gon Moon

doi:10.4048/jbc.2023.26.e1

AKR1C2 Promotes Metastasis and Regulates the Molecular Features of Luminal Androgen Receptor Subtype in Triple Negative Breast Cancer Cells

J Breast Cancer. 2023 Feb;26(1):60-76. doi: 10.4048/jbc.2023.26.e1. Epub 2022 Dec 16.

Authors

Songbin Li¹, Woochan Lee^{2

3}, Woohang Heo⁴, Hye-Youn Son⁴, Yujeong Her¹, Jong-Il Kim^{2

3}, Hyeong-Gon Moon^{5

6

7}

Affiliations

¹ Interdisciplinary Graduate Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
² Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
³ Genomic Medicine Institute, Medical Research Center, Seoul, Korea.
⁴ Center for Medical Innovation, Seoul National University Hospital, Seoul, Korea.
⁵ Cancer Research Institute, Seoul National University, Seoul, Korea.
⁶ Department of Surgery, Seoul National University Hospital, Seoul, Korea.
⁷ Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. moonhg74@snu.ac.kr.

Abstract

Purpose: Patients with triple-negative breast cancer (TNBC) have an increased risk of distant metastasis compared to those with other subtypes. In this study, we aimed to identify the genes associated with distant metastasis in TNBC and their underlying mechanisms.

Methods: We established patient-derived xenograft (PDX) models using surgically resected breast cancer tissues from 31 patients with TNBC. Among these, 15 patients subsequently developed distant metastases. Candidate metastasis-associated genes were identified using RNA sequencing. In vitro wound healing, proliferation, migration, and invasion assays and in vivo tumor xenograft and metastasis assays were performed to determine the functional importance of aldo-keto reductase family 1 member C2 (AKR1C2). Additionally, we used the METABRIC dataset to investigate the potential role of AKR1C2 in regulating TNBC subtypes and their downstream signaling activities.

Results: RNA sequencing of primary and PDX tumors showed that genes involved in steroid hormone biosynthesis, including AKR1C2, were significantly upregulated in patients who subsequently developed metastasis. In vitro and in vivo assays showed that silencing of AKR1C2 resulted in reduced cell proliferation, migration, invasion, tumor growth, and incidence of lung metastasis. AKR1C2 was upregulated in the luminal androgen receptor (LAR) subtype of TNBC in the METABRIC dataset, and AKR1C2 silencing resulted in the downregulation of LAR classifier genes in TNBC cell lines. The androgen receptor (AR) gene was a downstream mediator of AKR1C2-associated phenotypes in TNBC cells. AKR1C2 expression was associated with gene expression pathways that regulate AR expression, including JAK-STAT signaling or interleukin 6 (IL-6). The levels of phospho-signal transducer and activator of transcription and IL-6, along with secreted IL-6, were significantly downregulated in AKR1C2-silenced TNBC cells.

Conclusion: Our data indicate that AKR1C2 is an important regulator of cancer growth and metastasis in TNBC and may be a critical determinant of LAR subtype features.

Keywords: Aldo-Keto Reductase Family 1 Member C2; Neoplasm Metastasis; Receptors, Androgen; Triple Negative Breast Neoplasms.

Abstract

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