Abstract
BackgroundBreast cancer is a life-threatening disease in females and the leading cause of mortality among the female population, presenting huge challenges for prognosis and treatment. ITM2A is a member of the BRICHOS superfamily, which are thought to have a chaperone function. ITM2A has been identified to related to ovarian cancer progress recently. However, the biological role of ITM2A in breast cancer remains largely unclear.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR), western blotting assay and immunohistochemistry staining were used to analyzed the expression level of ITM2A. The patient overall survival versus ITM2A expression level was evaluated by Kaplan-Meier analysis. MTT assay, EdU incorporation assay and colony formation assay were used to evaluated the role of ITM2A on breast cancer cell proliferation. Autophagy was explored through autophagic flux detection using a confocal microscope and autophagic vacuoles investigation under a transmission electron microscopy (TEM). In vitro kinase assay was used to investigated the phosphorylation modification of ITM2A by HUNK.ResultsOur data showed that the expression of integral membrane protein 2A (ITM2A) was significantly down-regulated in human breast cancer tissues and cell lines. Kaplan-Meier analysis indicated that patients presenting with reduced ITM2A expression exhibited poor overall survival, and expression significantly correlated with age, progesterone receptor status, TNM classification and tumor stage. ITM2A overexpression significantly inhibited the proliferation of breast cancer cells. By studying several autophagic markers and events in human breast cancer SKBR-3 cells, we further demonstrated that ITM2A is a novel positive regulator of autophagy through an mTOR-dependent manner. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis.ConclusionOur study provided evidence that ITM2A functions as a novel prognostic marker and represents a potential therapeutic target.
Highlights
Breast cancer is a life-threatening disease in females and the leading cause of mortality among the female population, presenting huge challenges for prognosis and treatment
We found that the mRNA level of integral membrane protein 2A (ITM2A) was 7.40-fold down-regulated in breast cancer tissues (n = 1101) compared with that in normal tissues (n = 139) from the The cancer genome atlas (TCGA) database of breast cancer (Fig. 1a)
Through genome-wide expression analysis, we found that the mRNA level of ITM2A was 7.40-fold down-regulated in breast cancer tissues compared with the level in normal tissues
Summary
Breast cancer is a life-threatening disease in females and the leading cause of mortality among the female population, presenting huge challenges for prognosis and treatment. The biological role of ITM2A in breast cancer remains largely unclear. Breast cancer is the most prevalent malignancy worldwide and the second leading cause of cancer death for women. In 2018 alone, the estimated number of newly diagnosed cases and deaths from breast cancer in women in the United States were 266,120 and 40,920, respectively [1]. The identification of diagnostic markers and potential cellular and molecular mechanisms underlying breast cancer metastasis, as well as the development of new therapeutic strategies for improving patient survival and overall quality of life, are urgently needed [6]
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