Expression Of SETD7 In Breast Cancer And Its Effect On Proliferation And Migration Of Breast Cancer Cells

Background:Breast cancer is a high-risk disease in China.The study of pathological molecular typing of breast cancer shows that the diagnosis,treatment and healing of different molecular types are very different.Triple negative breast cancer has the worst prognosis.Primary and/or acquired drug resistance in patients with HER2 positive breast caner affects the therapeutic effect seriously.Previous studies have shown that abnormal histone methylation plays an important regulatory role in the development of tumors.It has been reported that SETD7 plays an important role in tumors such as colorectal cancer,liver cancer and prostate cancer.However,there are few reports on the mechanism of action of SETD7 in breast cancer.To study the specific expression of SETD7 in breast cancer and its effect on proliferation,migration and drug resistance;the specific role of inhibitor(R)-PFI-2 in breast cancer and the role of SETD7 in drug resistance may help to propose new possibilities for breast cancer treatment.Objective:To detect the expression of lysine methylase and demethylase in HER2over-expression and triple-negative breast cancer patients,and study the expression of SETD7 in breast cancer and its effect on proliferation,migration and drug resistance.To study the specific role of inhibitor(R)-PFI-2 in breast cancer.Method:1.The mRNA expression of 52 kind of lysine methylase and demethylase in breast cancer was tested by Real-time PCR.2.Real-time PCR and Western-blot was used to detect the expression of SETD7 in four different types of breast cancer tissues and cells.3.The effect of silencing and over-expression of SETD7 on breast cancer cell migration and proliferation was examined by the Wounding Healing Assay and CCK-8.Western-blot was used to detect the effect of silencing and overexpression of SETD7 on H3K4me1.4.CCK-8 was used to detect the effect of SETD7 inhibitor(R)-PFI-2 on proliferation of breast cancer and the effect of(R)-PFI-2 in combination with lapatinib on cell growth.5.The human HER2 positive lapatinib-resistant breast cancer cell models was established by low concentration gradient increment method.6.The expression of SETD7 in laptinib-resistant cells was tested by Real-time PCR.Resμlt:In the HER2 over-expressing breast cancer tissues,there were 32 kinds of lysine methylases and demethylases increased,10 of them did not differ markedly,and 12 were decreased.In the three-negative breast cancer tissues,there were 37 kinds of them were increased,3 of them did not differ markedly,and 12 were decreased.The increased or reduced expression may be therapeutic target for breast cancer.SETD7 was highly expressed in four different molecular type of breast cancer tissues,with the highest expression of the three negative types,followed by HER2over-expression,Luminal A and Luminal B.SETD7 is also highly expressed in four breast cancer cells SK-BR-3,BT474,MDA-MB-231,and MCF-7.Also found that H3K4me1 increased in breast cancer.The expression of H3K4me1 and the proliferation and migration of breast cancer cells can be inhibited by silencing SETD7.In contrast,over-expression SETD7 can promote the expression of H3K4me1 the proliferation and migration of breast cancer cells.At the same time,weverified that(R)-PFI-2,the small molecule inhibitor of SETD7 can inhibit the expression of SETD7 in breast cancer cells,it can also inhibit the proliferation of breast cancer cells.Then we found that(R)-PFI-2 in combination with lapatinib can enhance the growth inhibition of breast cancer cells.We found that SETD7 is highly expressed in SK-BR-3-LR and BT474-LR,which indicate that it may have important role in breast cancer lapatinib drug resistance.Conclusion:SETD7 is highly expressed in breast cancer and may affect the proliferation and migration of breast cancer cells by regulating H3K4me1.(R)-PFI-2 can inhibit breast cancer cell proliferation significantly.And(R)-PFI-2 in combination with lapatinib can enhance the growth inhibition of breast cancer cells.At the same time,it was found that SETD7 was highly expressed in lapatinib-resistant cell SK-BR-3-LR.