Estrogen Receptor Signal Pathway Attenuate The Sensitivity Of Nab-paclitaxel Through Inhibiting The Expression Of Caveolin1 In Breast Cancer

Background:Breast cancer accounts for the most malignant cancer among women,threatening women’s life and health seriously.Based on different gene expression characteristics,breast cancer can generally be divided into four molecular subtypes: hormone receptor-positive(Luminal A,Luminal B),Her2-positive,and Basal-Like.Currently,treatments in breast cancer usually include surgery,chemotherapy,radiotherapy,endocrine therapy,molecular targeted therapy and immunotherapy.Among them,endocrine therapy has become the cornerstone of hormone receptor(HR)-positive breast cancer treatment.However,chemotherapy is still the mainstay of treatment after resistance to endocrine therapy and visceral crisis.Recently,nab-paclitaxel has become the first-line treatment for advanced triple-negative breast cancer chemotherapy.However,the insufficient sensitivity of Nab-paclitaxel to estrogen receptor-positive breast cancer patients has received widespread attention with its mechanism not been fully elucidated.Objective:We aim to elucidate the effect of ER signaling pathway on the sensitivity of Nab-paclitaxel and try combined with ER signal pathway inhibitors to increase the treatment efficacy of Nab-paclitaxel.To confirm that Caveolin1 is involved in regulation of Nab-paclitaxel sensitivity in breast cancer.To reveal the regulatory effect of ER signaling pathway on Caveolin1 and its specific molecular mechanism.Method:MTS experiments were used to verify the sensitivity differences between triple negative breast cancer(TNBC)cell lines and HR-positive breast cancer cell lines to Nab-paclitaxel and the sensitizaiton effect of ER signal pathway inhibitors(Tamoxifen,Fulvestrant)to Nab-paclitaxel in HR-positive breast cancer cells;Western Blot was used to study the differential expressions of apoptotic proteins caused by treated with ER signal pathway inhibitors(Tamoxifen,Fulvestrant)combined with Nab-paclitaxel;Western Blot was used to detect effect of knockdown of estrogen receptor ERα and treatment with ER signal pathway inhibitors(Tamoxifen,Fulvestrant)on the regulation of Caveolin1 expression;MTS experiments were used to detect the effect of knockdown or overexpression of Caveolin1 on the sensitivity of Nab-paclitaxel after transfection of si RNA or overexpressed plasmid;Quantitative PCR was used to clarify the differences of Caveolin1 m RNA expression after knockdown of estrogen receptor ERa and treatment with ER signal pathway inhibitors(Tamoxifen,Fulvestrant)in HR-positive breast cancer cells on Caveolin1 m RNA expression;the nascent peptide detection translation experiments were used to detect the effect of knockdown ERαon Caveolin1translation;the effect of inhibiting the estrogen receptor signaling pathway on the degradation of Caveolin1 protein was tested using half-life experimentsResults:The sensitivity of ER-positive breast cancer cells to Nab-paclitaxel is significantly lower than triple-negative breast cancer cells;ER signal pathway inhibitors(Tamoxifen,Fulvestrant)can reverse the insensitivity of Nab-paclitaxel in ER-positive breast cancer;knockdown of Caveolin1 inhibits the sensitivity of Nab-paclitaxel in breast cancer;Overexpression caveolin 1 enhances sensitivity of Nab-paclitaxel.Caveolin1 protein expression in ER-positive breast cancer cells is lower than triple-negative breast cancer cells.Knockdown of ERαand treatment with ER signal pathway inhibitors(Tamoxifen,Fulvestrant)can upregulate Caveolin1 protein expression,but have no significant effect on its transcriptional level,protein half-life and protein degradation;knocking down of ERαcan enhance the translational efficiency of Caveolin1 nascent protein.Conclusion:ER signaling pathway attenuates the sensitivity of Nab-paclitaxel in Estrogen receptor positive breast cancer through reducing the translation of Caveolin1,leading to a decrease in endocytosis of Nab-paclitaxel.Combined with ER signal pathway inhibitors can effectively enhance the sensitivity of Nab-paclitaxel to ER-positive breast cancer.