Downregulation of CYB5D2 is associated with breast cancer progression

Diane Ojo,David Rodriguez,Damu Tang,Anita Bane,Fengxiang Wei

doi:10.1038/s41598-019-43006-y

Abstract

We report here that CYB5D2 is associated with tumor suppression function in breast cancer (BC). CYB5D2 expression was significantly reduced in tamoxifen resistant MCF7 cells and in MCF7 cell-derived xenografts treated with TAM. CYB5D2 overexpression induced apoptosis in MCF7 cells; CYB5D2 knockdown enhanced MCF7 cell proliferation. Using the TCGA and Curtis datasets within the Oncomine database, CYB5D2 mRNA expression was downregulated in primary BCs vs breast tissues and HER2-positive or triple negative BCs vs estrogen receptor (ER)-positive BCs. Using the TCGA and Metabric datasets (n = 817 and n = 2509) within cBioPortal, 660 and 4891 differentially expressed genes (DEGs) in relation to CYB5D2 were identified. These DEGs were enriched in pathways governing cell cycle progression, progesterone-derived oocyte maturation, oocyte-meiosis, estrogen-mediated S-phase entry, and DNA metabolism. CYB5D2 downregulation decreased overall survival (OS, p = 0.0408). A CYB5D2-derived 21-gene signature was constructed and robustly correlated with OS shortening (p = 5.72e-12), and independently predicted BC deaths (HR = 1.28; 95% CI 1.08–1.52; p = 0.004) once adjusting for known clinical factors. CYB5D2 reductions displayed relationship with mutations in PIK3CA, GATA3, MAP3K1, CDH1, TP53 and RB1. Impressively, 85% (560/659) of TP53 mutations occurred in the 21-gene signature-positive BC. Collectively, we provide the first evidence that CYB5D2 is a candidate tumor suppressor of BC.

Highlights

Breast cancer (BC) is a major cause of cancer related deaths in women
Our recent identification of CYB5D2 as a tumor suppressor in cervical cancer[11] as well as its genomic location at 17p13.2; this region is frequently lost in breast cancer[29]; led us to study the possible involvement of CYB5D2 in BC
The downregulation was demonstrated in MCF7 cell-derived xenograft tumors treated with TAM compared to xenografts produced in untreated mice by either real-time PCR (Fig. 1C) or IHC (Fig. 1D)

Summary

Introduction

Breast cancer (BC) is a major cause of cancer related deaths in women. Annually, there are approximately 1.7 million new cases and more than 500,000 fatalities[1]. CYB5D2 (cytochrome b5 domain containing 2) was reported as a new tumor suppressor in cervical cancer[11]. PGRMC2 was able to inhibit ovarian cancer (SKOV-3) cell migration in vitro[27], and its downregulation was observed in metastatic endocervical adenocarcinomas of uterus[28], suggesting the protein as a tumor suppressor. The CYB5D2 gene resides at 17p13.2; 17p13.2–13.3 is lost in 50% of breast cancer[29], indicating that CYB5D2 may be a novel tumor suppressor of BC In support of this possibility, we report here a significant reduction of CYB5D2 expression following the progression of tamoxifen resistance both in vitro and in vivo as well as in more than 3000 primary BCs. CYB5D2 downregulation is correlated with mutations in PIK3CA, GATA3, MAP3K1 and TP53 as well as reductions in overall survival (OS) of breast cancer

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