Role Of ErbB3 Overexpression In Tumor Metastasis Of ErbB2-positive Breast Cancer And Its Preliminary Molecular Mechanisms

Female breast cancer is a major type of malignant tumor developed from the ductal epithelium of the breast.It has long been the most commonly diagnosed cancer in female worldwide.The age of patient with breast cancer tends to be younger on its first diagnosis recently.With the deepening of the research,the understanding of the molecular mechanisms of breast cancer development is also increasing.Based on the newly unveiled molecular mechanisms underlying the tumorigenesis and development of breast cancer,treatment strategies such as targeted therapy and immunotherapy has constantly enrich the comprehensive treatment of breast cancer;however,so far it is still a serious disease endangering the health of women worldwide.Due to the heterogeneity of tumors and the different malignant biological characteristics of different molecular subtypes of breast cancer,some patients still show aggressive tumor growth and may form distant metastasis after comprehensive treatment.In fact,a large number of studies have shown that about 90%of breast cancer deaths are due to the involvement of distant target organ metastasis.At present,our understanding of the molecular mechanism of breast cancer metastasis is still very limited,and the corresponding effective intervention measures are lack of,so the metastatic tumor is still a refractory category.Among the various molecular subtypes of breast cancer,ErbB2-positive breast cancer accounts for about 25-30%of all breast cancer,and tumors in patients with this molecular subtype of breast cancer tend to grow aggressively and metastasize.Unfortunately,until now the exact molecular mechanism is unclear.In our previous studies,we found that ErbB3 overexpression plays an important role in development of both chemotherapy and targeted therapy resistance in ErbB2-positive breast cancer.In our current study,our further exploration showed that ErbB3 overexpression not only significantly promoted the growth and proliferation of ErbB2-positive breast cancer,but also significantly enhanced its invasion and migration.The preliminary mechanism investigation showed that ErbB3 overexpression could not only significantly induce the up-regulation of transcription factors such as ZEB1 in ErbB2-positive breast cancer cells to promote the EMT phenotype,but also significantly promote the up-regulation of MMP2 and MMP9 expressions with activation of downstream Akt and MAPK signalling pathways at the same time.In addition,RT-qPCR analysis also confirmed that ErbB3 overexpression down-regulated the expression of miR-203 and miR-542-3p,both of which may target ZEB1 and other EMT-regulating transcription factors.Analysis of clinical samples preliminarily suggested that ErbB3 overexpression may be associated with clinical metastasis in patients with ErbB2-positive breast cancer.In conclusion,our study suggests that overexpression of ErbB3 may play an important role in promoting the metastasis of ErbB2-positive breast cancer.Whether ErbB3 can be used as a new candidate target for development of targeted intervention against metastasis in ErbB2-positive breast cancer is worthy of further investigation.