| Previous studies have shown that hormone can directly or indirectly affect the biological behavior of tumors.Estrogen and progesterone dependent breast cancer and androgen dependent prostate cancer arethe most common types of hormone dependent tumors,there are some similarities in the mechanisms of tumor metastasis and resistance to hormone therapy.Therefore,identifying genes involved in the regulation of cancer metastasis and/or treatment resistance in breast cancer and prostate cancer and exploring the molecular mechanisms are of great significance for the "treatment of different diseases with the same method" of these two tumors.Gab(growth factor receptor binding protein 2,Grb2)is an important scaffolding protein with high evolutionary conservativeness.There are five members of the Gab family,including Gab1,Gab2,Gab3 from mammals,Dos from Drosophila melanogaster,and Soc1 Caenorhabditis elegans.Gab family plays an important role in signal transduction,and acts as “signal amplifier” through its involvement in various signal pathways.In addition,the abnormal expression of Gab protein is closely related to the growth and progression of various tumors,such as melanoma,ovarian cancer,head and neck squamous cell carcinoma,colorectal cancer and so on.Previous studies have shown that abnormal expression and localization of Gab2 can promote the occurrence and development of breast cancer.However,as the most abundant protein of Gab family protein in mammals,it is unclear whether and how Gab1 regulates the growth,metastasis and treatment resistance of breast and/or prostate cancer.Breast cancer metastasis is still the most leading cause of death in female cancer patients worldwide.Due to the lack of effective biomarkers for diagnosis of metastasis,about 6% of patients were found to have metastatic diseases at the first diagnosis.Therefore,screening and identifying early diagnostic markers of breast cancer metastasis,especially those applicable to various subtypes of breast cancer,is of great significance for diagnosis and treatment of diseases.In this study,we found that the expression of Gab1 was significantly increased in breast cancer.Furthermore,Gab1 expression was positively correlated with breast cancer metastasis in HER2 and triple negative breast cancer patients.Overexpression of Gab1 in HER2 breast cancer cell line SK-BR3 and triple negative breast cancer cell line MDA-MB-231 can promote tumor metastasis in vitro and in vivo,whereas knockdown of Gab1 can inhibit tumor metastasis.In the study of molecular mechanism,we found that overexpressed Gab1 can dissociate PAR polar complexes by enhancing the interaction with polarity protein Par3 and Par1 b,thus inducing epithelial-to-mesenchymal transition(EMT)to promote breast cancer metastasis.These results suggest that Gab1 may be a new common diagnostic marker for metastasis in different subtypes of breast cancer.It also suggests that Gab1 may be a potential therapeutic target for breast cancer metastasis.Advanced prostate cancer,especially relapse of castration resistant prostate cancer after androgen deprivation therapy(ADT),is the main cause of death in cancer patients.Therefore,it is of great clinical significance and value to study the mechanism of resistance to hormone therapy in prostate cancer.In this study,we found that the endogenous expression of Gab1 was significantly increased in androgen-independent prostate cancer cell lines.In vitro,the expression of Gab1 in androgen-sensitive prostate cancer cell line LNCaP was significantly increased after being cultured in androgen-free medium.Overexpression of Gab1 in LNCaP cells can significantly enhance the ability of three-dimensional spheroidization of tumor cells in de-androgenic culture medium.In mechanism research,through high-throughput protein interaction mass spectrometry,we found that Gab1 can promote the activation of YB1 by interacting with transcription factor YB1,inducing the expression of SYP,CHGA and other genes related to prostatic neuroendocrine,and mediated the activation of PI3K/AKT and other signal pathways related to tumor proliferation,leading to epithelial-neuroendocrine-like(ENT)transformation of adenocarcinoma cells and result in resistance to ADT.These results suggest that Gab1 overexpression can promote resistance to ADT in prostate cancer,and inhibition of Gab1 expression can be used as a new adjuvant therapy to improve the efficacy of ADT for prostate cancer.In conclusion,the results of this study suggest that Gab1 may be a new potential therapeutic target for the development of novel targeted drugs for breast cancer and prostate cancer.The results of this study also provide theoretical foundation for the "treatment of different diseases with the same method" of the two kinds of tumors. |
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