ER? And ER?36 Predict Outcome Of Breast Cancer And Inactivate PI3k/AKT Pathway By Upregulating PTEN

Backgroud:Estrogen receptors(ERs)play important roles in the occurrence and development of breast cancer.ERs are divided into two subtypes,ER? and ER?.ER? has three variants: ER?66,ER?46 and ER?36.ER?66,the traditional estrogen receptor,was closely linked with breast cancer and has become the most important marker for clinical endocrine therapy of breast cancer.ER?36 was a variant of ER?66.Many studies have demonstrated that ER?36 promotes the invasion and metastasis of breast cancer and plays an important role in resistance to endocrine therapy.ER? has five variantss.Studies suggested that ER? could inhibit the development of breast cancer,but the mechanism was poorly understood.ER? and ER?36 have opposite effect in breast cancer,but the relationship between their expression and prognostic significance in breast cancer has not yet been studied.It has been reported that ER?36 promotes breast cancer cell proliferation and invasion mainly by activating PI3K/AKT pathway,while ER? can inactivate PI3K/AKT pathway by upregulating PTEN.However,it needs more experimental evidence.Objective:1.To clarify the relationship between expression of ER? and ER?36 and prognosis significance in breast cancer;2.To definite ER? could inhibite the proliferation of breast cancer cells by upregulating PTEN to inactivate PI3K/AKT pathway.Methods:1.The expressions of ER? and ER?36 was used to detected in breast cancer specimens by the manner of Immunohistochemitry(IHC),and the relationship between their expression and patients' prognosis was analyzed.2.IHC was used to examine the expression of PTEN in breast cancer specimens,and the relationship between their expression and patients' prognosis was analyzed.3.Activated ER? in breast cancer cells,detection the changes of PTEN protein expression and PI3K/AKT pathway activation state.Results:1.An inverse correlation between ER? and ER?36 expression was observed;the combination of ER? and ER?36 expression status improves the prognostic judgment.(1)The expression of ER? and ER?36 is inverse(r=-0.42,P <0.01).(2)The expression of ER? was inversely associated with TNM stage(P=0.003)and lymph node metastasis(P = 0.007),whereas ER?36 expression was positively correlated with TNM stage(P = 0.001)and tumor size(P = 0.029).(3)Patients with ER?-positive exhibited better disease-free survival rate than those with ER?-negative(P=0.005).Conversely,patients with ER?36-positive exhibited poorer disease-free survival rate than those with ER?36-negative(P=0.029).ER?-negative/ ER?36-positive patients had the poorest disease-free survival rate(P= 0.018).(4)Cox regression analysis showed that ER? was a protective prognostic factor(HR = 0.336,p = 0.026),and ER?36 was a poor prognostic indicator(HR = 2.737,P = 0.029).2.The function of ER? and ER?36 on PI3K/AKT pathway was inverse.(1)The expression of ER? and PTEN is positive correlation(r =0.68,P<0.01).(2)ER? can inactivate phosphorylation of AKT by upregulating PTEN in breast cancer cells.Conclusion: Our results demonstrate that the levels of ER? and ER?36 expression inversely predict the outcome of breast cancer patients and the combination of ER? and ER?36 expression status improves the prognostic judgment.The expression of ER? and PTEN is positive correlation.ER? could inhibite the proliferation of breast cancer cells by upregulating PTEN.