The Function And Mechanism Study Of Shikonin Reducing Tamoxifen Resistance Through Long Non-coding RNA Uc.57 In Breast Cancer

Breast cancer is the most common kind of solid tumors among female,The incidence number of breast cancer in our country is increasing at 270 thousands per year during the recent decade,and the mortality caused by breast cancer is the first in female tumors.Endocrine therapy is one of the most important treatment to ER positive breast cancer patients,and tamoxifen is the main medicine of the of endocrine therapy.Tamoxifen has achieved remarkable success in decreasing recurrence and metastasis rate of ER positive breast cancer patients and prolonging their survive time.But the resistance to tamoxifen has become a serious clinical problem,causing recurrence and metastasis even death.Therefore exploring the mechanism of tamoxifen resistance,searching for new strategy to overcome it possesses great significance to breast cancer treatment.Shikonin(SK)is an active ingredient isolated from the Chinese herb,Lithospermum erythrorhizon,which has been used for thousands of years in traditional Chinese medicine.It exerts anti-inflammatory,wound healing,and anti-cancer effects.SK inhibits estrogen-dependent tumor cell growth and promotes the anti-estrogen effect of endocrine therapy in breast cancer.It modulates mitogen-activated protein kinase(MAPK)and phosphoinositide 3-kinase(PI3K)pathways to suppress growth and survival of the malignant tumor cells.MAPK and PI3 K pathways are critical players in TAM resistance and their inhibition promotes TAM sensitivity.This suggests that SK would be therapeutically beneficial to reduce TAM resistance in breast cancer cells.Long non-coding RNAs(lncRNAs)are non-protein encoding transcripts that are longer than 200 nucleotides that are involved in tumorigenesis by post-transcritpionalregulation of oncogenes and tumor suppressors.LncRNAs are involved in TAM resistance via numerous mechanisms in addition to estrogen receptor(ER)signaling.Many lncRNAs are conserved in humans and have potential clinical applications in anti-tumor therapy.In this study,we revealed the involvement of lncRNA uc.57 and its downstream gene BCL11 A in TAM resistance.Tamoxifen-resistant MCF-7R cells showed lower expression of uc.57 and higher expression of BCL11 A m RNA and protein than the parental MCF-7 cells.Moreover,levels of uc.57 m RNA were lower and BCL11 A m RNA were higher in breast cancer tissues than in precancerous breast tissues.Shikonin treatment reduced tamoxifen resistance in MCF-7R cells both in vitro and in vivo,targeting uc.57/BCL11 A.Fluorescence in situ hybridization and RNA immunoprecipitation analyses showed that uc.57 binds to BCL11 A.Uc.57 overexpression downregulated BCL11 A and reduced tamoxifen resistance in MCF-7R cells both in vitro and in vivo.BCL11 A knockdown also reduced tamoxifen resistance by inhibiting PI3K/AKT and MAPK signaling pathways.It thus appears shikonin reduces tamoxifen resistance of MCF-7R breast cancer cells by inducing uc.57,which downregulates BCL11 A to inhibit PI3K/AKT and MAPK signaling pathways.