Elevation of SIPL1 (SHARPIN) Increases Breast Cancer Risk.

Abstract

SIPL1 (Sharpin) or Sharpin plays a role in tumorigenesis. However, its involvement in breast cancer tumorigenesis remains largely unknown. To investigate this issue, we have systemically analyzed SIPL1 gene amplification and expression data available from Oncomine datasets, which were derived from 17 studies and contained approximately 20,000 genes, 3438 breast cancer cases, and 228 normal individuals. We found a SIPL1 gene amplification in invasive ductal breast cancers compared to normal breast tissues and a significant elevation of SIPL1 mRNA in breast cancers in comparison to non-tumor breast tissues. These results collectively reveal that increases in SIPL1 expression occur during breast cancer tumorigenesis. To further investigate this association, we observed increases in the SIPL1 gene and mRNA in the breast cancer subtypes of estrogen receptor (ER)+, progesterone receptor (PR)+, HER2+, or triple negative. Additionally, a gain of the SIPL1 gene correlated with breast cancer grade and the levels of SIPL1 mRNA associated with both breast cancer stages and grades. Elevation of SIPL1 gene copy and mRNA is linked to a decrease in patient survival, especially for those with PR+, ER+, or HER2- breast cancers. These results are supported by our analysis of SIPL1 protein expression using a tissue microarray containing 224 breast cancer cases, in which higher levels of SIPL1 relate to ER+ and PR+ tumors and AKT activation. Furthermore, we were able to show that progesterone significantly reduced SIPL1 mRNA and protein expression in MCF7 cells. As progesterone enhances breast cancer tumorigenesis in a context dependent manner, inhibition of SIPL1 expression may contribute to progesterone's non-tumorigenic function which might be countered by SIPL1 upregulation. Taken together, we demonstrate a positive correlation of SIPL1 with BC tumorigenesis.