Abstract
Abstract Background: SIPA1 (signal-induced proliferation-associated protein 1) encodes for a GTPase-activating protein, known to be a negative regulator of Ras-related Protein (RAP1). It has been implicated in cancer invasion and metastasis, including cervical cancer, breast cancer and colorectal cancer. In our previous study of SIPA1 activates the integrin beta1 to promote metastasis, we found that SIPA1 may effect series of surface adhesive protein expression, including an important glyco-protein, CD44. CD44 is reported as a critical marker of breast cancer stem cells, so we hypothesis that SIPA1 may induce the stemness in breast cancer through regulating the expression of CD44. Methods: We examined the relationship between the expression of SIPA1 and CD44 in breast cancer tissues and different breast cancer cell lines. Then we used the knockdown of SIPA1 in MDA-MB-231 and an overexpression in the MDA-MB-361 to examine the effects of SIPA1 expression to CD44 in breast cancer cell lines. In vitro tumorigenic properties of SIPA1 high cells were characterized with sensitivity to 5FU and the ability to form tumorspheres, the expression of cancer stem cell markers, including CD44, CD24, ALDH, and the proportion. In vivo analysis used a tissue microarray chip with clinicopathologic features and survival data from 240 breast cancer patients were reviewed with immunohistochemistry (IHC) against SIPA1. Results: In vitro studies showed that SIPA1 high cells with a high level of CD44 expression. They displayed an obviously EMT phenotype, and found to have a higher ability to form tumor spheres, improved expression level of breast cancer stem cell markers, increased resistance to 5FU, and decreased in the cell proliferation. SIPA1 may induce cancer stem cell features through the expression of CD44 and induced the EMT through CD44-PI3K-Akt pathway with a changed CD44 splicing isoform pattern. Studies with breast cancer tissues showed that SIPA1 expressed in the in situ breast cancer, while SIPA1 and CD44 are co-expressed in the metastasis breast cancer. The Kaplane-Meier survival analysis of 240 breast cancer samples found that SIPA1 negative-associated with breast cancer survive (p = 0.003) and prognosis (p = 0.002), and the Cox's proportianal hazard model analysis of prognostic factors in patients with potentially curatively treated breast cancer showed that SIPA1 expression correlated with 5 disease free survive(p = 0.047) and 5 year overall survive(p = 0.015). Conclusion: Taking together, our data suggest that SIPA1 induced CD44 expression in breast cancer cells, SIPA1/CD44high cells display stemness and EMT phenotype, and found to be more resistance to 5FU with a decreased proliferation ability. SIPA1 expression contributes to the survival and prognosis of breast cancer. Further studies to investigate how SIPA1 promotes CD44 expression are needed. Citation Format: Li Su, Jing Xia. SIPA1 negatively regulates the survive in breast cancer patients and promotes CD44 expression to drive cancer cell stemness. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2245. doi:10.1158/1538-7445.AM2015-2245
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