The Mechanism Of PTEN Mediated PI3K/AKT/mTOR Signaling Pathway Regulating Autophagy Influencing Docetaxel Resistance In Triple Negative Breast Cancer

Background:Breast cancer is one of the most common malignancies in women and triplenegative breast cancer(TNBC)is the most malignant and aggressive subtype of breast cancer.As there are no known targeted drugs,the mainstay of treatment for triple-negative breast cancer is conventional chemotherapy,with proven efficacy.Docetaxel is one of the first-line chemotherapeutic agents in the clinic,but due to the toxicity and non-selectivity of chemotherapeutic agents,after a period of treatment,tumours can accumulate mutations and develop acquired drug resistance as cancer progresses and is treated.The PI3K/AKT/mTOR signalling pathway is considered to be a key pathway affecting tumour development and progression,and is closely linked to the oncogenesis of various malignancies.It has been shown that tumour development in breast cancer is dependent on the PI3K/AKT/mTOR pathway.By establishing a drug-resistant triple-negative breast cancer cell model,we will explore the mechanism of docetaxel resistance and provide new ideas for the clinical management of triple-negative breast cancer.Objectives:The expression of the PTEN and PI3K/AKT/mTOR pathways in normal triplenegative breast cancer cells was compared with that in docetaxel-resistant triplenegative breast cancer cells.This study aims to elucidate the mechanism of acquired resistance to docetaxel via the PTEN-PI3K/AKT/mTOR regulatory pathway and to provide a rationale for the prevention and resolution of docetaxel resistance in triple negative breast cancer patients.Methods:1 Establishment of docetaxel-resistant cells in triple-negative breast cancer MDA-MB-231/DTX.The autophagic structure was observed by transmission electron microscopy,and the proliferation migration of MDA-MB-231 and MDA-MB-231/DTX,a docetaxel-resistant cell from triple-negative breast cancer,was detected by CCK-8,cell colony assay and cell scratch assay.2 RT-qPCR and Western blotting were used to determine the mRNA and protein expression of PTEN/PI3K/AKT/mTOR,while Western blotting was used to detect phosphorylated PI3K/AKT/mTOR.3 The autophagic structure was observed by transmission electron microscopy and the protein expression of autophagy-related markers LC3 and Beclin-1 was detected by Western blotting.4 Cellular autophagy was observed using the 3-MA and the rapamycin.Results:Docetaxel inhibits autophagy and induces resistance to MDA-MB-231 through activation of the PI3K/AKT/mTOR signalling pathway by PTEN;Conclusions:1 Constructs of successful docetaxel-resistant cells MDA-MB-231/DTX from triple-negative breast cancer were consistent with the addition of docetaxel to normal MDA-MB-231 cells.2 Docetaxel mediated resistance to MDA-MB-231 in breast cancer cells via the PTEN-mediated PI3K/AKT/mTOR signalling pathway.3 Docetaxel inhibits autophagy through the PTEN-mediated PI3K/AKT/mTOR signalling pathway and induces drug resistance in MDA-MB-231 cells.When autophagy was inhibited in MDA-MB-231 cells,apoptosis was increased and proliferation and metastasis were correspondingly downregulated.4 By regulating the level of autophagy in MDA-MB-231 cells,autophagy was found to be associated with the sensitivity of docetaxel to MDA-MB-231 cells.