Squalene epoxidase expression is associated with breast tumor progression and with a poor prognosis in breast cancer

Abstract

Differentially expressed genes (DEGs) have been previously identified using massive parallel RNA sequencing in matched normal, breast cancer (BC) and nodal metastatic tissues. Squalene epoxidase (SQLE), one of these DEGs, is a key enzyme in cholesterol synthesis. The aim of the present study was to investigate the potential involvement of SQLE in the tumorigenic process of BC and to determine its association with the clinical outcome of BC. SQLE mRNA expression was measured using reverse transcription-quantitative PCR in 10 pairs of ductal carcinoma in situ (DCIS) and BC tissues and their adjacent normal tissues. Immunohistochemical staining of SQLE on tissue microarray was performed in 26 normal breast, 79 DCIS and 198 BC samples. The role of SQLE as a prognostic biomarker in patients with BC has been verified using BreastMark. SQLE mRNA expression was significantly increased in DCIS and BC tissues compared with that in their adjacent normal tissues. High SQLE expression was detected in 0, 48.1 and 40.4% of normal breast, DCIS and BC tissues, respectively. SQLE expression in DCIS and BC tissues was significantly higher than that in normal breast tissues. High SQLE expression was observed in DCIS with higher nuclear grade, comedo-type necrosis and HER2 positivity. High SQLE expression in BC was associated with larger tumor size, nodal metastases, higher stage, HER2 subtype and distant metastatic relapse. High SQLE expression was associated with poor disease-free and overall survival, and independently predicted poor disease-free survival in patients with BC. Following BreastMark analysis, high SQLE mRNA expression in BC was significantly associated with a poor prognosis in the ‘all’, lymph node negative, lymph node positive, luminal A subtype and luminal B subtype groups. Therefore, SQLE expression may be upregulated during the tumorigenic process of BC, and high SQLE expression may be a useful biomarker for predicting a poor prognosis in patients with BC.

Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression

“…In line with this proteomic data, we validated decreased levels of ALCAM and several of its targets (namely EPHA2 , FLNB, PLAU ), and of SEMA3C and SQLE following HMGCL silencing (Fig EV3B–D). Interestingly, ALCAM positively regulates cell adhesion, migration, and invasion of endometrial cancer cells (Devis et al , 2017), and SQLE, a rate‐limiting enzyme in the cholesterol biosynthesis pathway, promotes invasiveness of hepatocellular carcinoma (Sui et al , 2015) and tumor aggressiveness in breast cancer patients (Kim et al , 2021). Indeed, we observed that increased expression of ALCAM and SQLE in sg‐HMGCL PANC‐1 cells (Appendix Fig S3L and M, and Fig EV3E) does not alter cell proliferation (Appendix Fig S3N) but does restore the ability of these cells to migrate (Fig EV3F and G) and to form well‐aggregated spheroids (Fig EV3H) with invasive capacities (Fig EV3I).…”

“…We further compared the proteome of sg-CTRL and sg-HMGCL PANC-1 cells to identify changes in protein expression associated with loss of 3D-associated oncogenic features following HMGCL disruption. Among downregulated proteins upon HMGCL loss, we identified ALCAM, SEMA3C, FLNC, and GBP1/3 involved in tumor cell migration, invasion, cell-to-cell adhesion, and cytoskeleton homeostasis (Bagci et al, 2009;Li et al, 2017;Honkala et al, 2019;Kamil et al, 2019;Ni et al, 2021), and SQLE, MSMO1, and DHCR24 that belong to sterol metabolism (Fig 3G, Appendix Table S3). In line with this proteomic data, we validated decreased levels of ALCAM and several of its targets (namely EPHA2, FLNB, PLAU), and of SEMA3C and SQLE following HMGCL silencing (Fig EV3B -D).…”

Construction and Validation of a Novel Ferroptosis-Related Prognostic Model for Acute Myeloid Leukemia

“…Cholesterol metabolism plays an important role in the regulation of tumor biological processes, including ferroptosis, and a large number of investigators were devoted to exploring the maximum potential of cholesterol metabolism in tumor-targeted therapy ( Xu et al, 2020 ). As a key rate-limiting enzyme of cholesterol metabolism, SQLE , has been closely connected with the proliferation and metastasis of various cancers and has been used to predict poor prognosis, such as in nonalcoholic fatty liver disease-induced hepatocellular carcinoma, nasopharyngeal carcinoma, lung squamous cell carcinoma, and breast cancer ( Liu et al, 2018 ; Ge et al, 2019 ; Li L. et al, 2020 ; Kim et al, 2021 ). PGD is an enzyme that mediates the third step of the pentose phosphate pathway (PPP) and is overexpressed in multiple tumor cells, promoting the proliferation, survival, and metastasis of tumor cells through reprogrammed tumor bioenergetics.…”

Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy

“…Various cancers have been found to exhibit high levels of SQLE protein/mRNA or have SQLE copy number alterations (13). As an oncogene for breast cancer, gene amplification and overexpression of SQLE have been reported in cancer tissues/ ductal carcinoma in situ tissues compared with normal tissues (14)(15)(16)(17). Race expression differences have been reported: the expression of SQLE in African-Americans is higher than that in Caucasians in luminal A breast tumors and basal-like breast cancers (18,19).…”