SALL4 promotes tumor progression in breast cancer by targeting EMT

Abstract

Sal‐like protein 4 (SALL4) is overexpressed in breast cancer and might contribute to breast cancer progression, but the molecular mechanism remains unknown. Here, we found that within a group of 371 ethnic Chinese breast cancer patients, SALL4 was associated with lower grade (P = .002) and progesterone receptor positivity (P = .004) for overall cases; lower Ki67 (P = .045) and high vimentin (P = .007) for luminal cases. Patients with high SALL4 expression in lymph node metastasis showed a significantly worse survival than those with low expression. Knockout of SALL4 in a triple‐negative breast cancer cell line MDA‐MB‐231‐Red‐FLuc‐GFP led to suppressed ability in proliferation, clonogenic formation, migration, and mammosphere formation in vitro, tumorigenicity and lung colonization in vivo. On the other hand, overexpression of SALL4 enhanced migration and mammosphere formation in vitro and tumorigenicity in vivo. Mechanistically, there was a positive correlation between SALL4 expression and mesenchymal markers including Zinc finger E‐box binding homeobox 1 (ZEB1), vimentin, Slug, and Snail in vivo. Chromatin immunoprecipitation experiment indicated that SALL4 can bind to the promoter region of vimentin (−778 to −550 bp). Taken together, we hypothesize that SALL4 promotes tumor progression in breast cancer by inducing the mesenchymal markers like vimentin through directly binding to its promoter. Increased SALL4 level in metastatic lymph node relative to the primary site is an important poor survival marker in breast cancer.

SALL Proteins; Common and Antagonistic Roles in Cancer

“…Consistent with the previous results, in vivo studies indicated that vimentin regulation by SALL4 enhances EMT, mammosphere formation, and tumorigenicity. SALL4 deficiency reduced lung colonization in MDA-MB-231 cells [ 142 ] and was associated with triple-negative (ER-, PR-, and HER2-) phenotypes [ 143 ]. Nevertheless, a recent study from 371 breast cancer patients showed that SALL4 expression positively correlates with PR protein level.…”

“…Nevertheless, a recent study from 371 breast cancer patients showed that SALL4 expression positively correlates with PR protein level. PR was related to breast cancer stemness in vitro, similar to SALL4 [ 142 ]. For an extensive review on SALL4 and breast cancer, refer to [ 143 ].…”

Advances in Targeting Cancer-Associated Genes by Designed siRNA in Prostate Cancer

“…It was reported that silencing RPS7 using specific siRNA attenuates prostate tumor growth and migration, associated with upregulation in E-cadherin and downregulation in N-cadherin and Snail [50]. Sal-like 4 is a transcription factor that is upregulated in several types of cancers [51]. Research revealed that targeting Sal-like 4 with specific siRNA decreases proliferation and colony formation, and induces apoptosis in PCa C4-2 cells, likely through regulation of the expression of Bcl-2 and Bax [52].…”

Co-expression of cancer stem cell markers, SALL4/ALDH1A1, is associated with tumor aggressiveness and poor survival in patients with serous ovarian carcinoma

“…Studies in cancer also indicated that overexpression of SALL4 can increase the proliferation, migration, and invasion of cancer cells through targeting epithelial mesenchymal transition (EMT) [ 26 , 28 , 29 ]. Moreover, high expression of SALL4 is related to low survival and has been noticed as a prognostic factor in the patients with BC and gliomas [ 24 , 25 ].…”