Abstract
Currently, there is no effective molecular-based therapy for triple-negative breast cancer (TNBC). Canonical transient receptor potential isoform 3 (TRPC3) was previously shown to be upregulated in breast cancer biopsy tissues when compared to normal breast tissues. However, the biological role of TRPC3 in breast cancer still remains to be elucidated. In this study, subcellular fractionation followed by Western blot and immunocytochemistry showed that TRPC3 was over-expressed on the plasma membrane of TNBC line MDA-MB-231 when compared to an estrogen receptor-positive cell line MCF-7. TRPC3 blocker Pyr3 and dominant negative of TRPC3 attenuated proliferation, induced apoptosis and sensitized cell death to chemotherapeutic agents in MDA-MB-231 as measured by proliferation assays. Interestingly, Ras GTPase-activating protein 4 (RASA4), a Ca2+-promoted Ras-MAPK pathway suppressor, was found to be located on the plasma membrane of MDA-MB-231. Blocking TRPC3 decreased the amount of RASA4 located on the plasma membrane, with concomitant activation of MAPK pathways. Our results suggest that, in TNBC MDA-MB-231 cells, Ca2+ influx through TRPC3 channel sustains the presence of RASA4 on the plasma membrane where it inhibits the Ras-MAPK pathway, leading to proliferation and apoptosis resistance. Our study reveals the novel TRPC3-RASA4-MAPK signaling cascade in TNBC cells and suggests that TRPC3 may be exploited as a potential therapeutic target for TNBC.
Highlights
Breast cancer is one of the leading heterogeneous diseases in women worldwide which can be divided into several subtypes [1,2]
We aimed to investigate if TRPC3 is responsible for the proliferation and apoptosis resistance of the triple-negative breast cancer (TNBC) cells, and, if yes, the underlying mechanisms involved
The expression of TRPC3 in MCF-7 and MDA-MB-231 was examined by Western blot
Summary
Breast cancer is one of the leading heterogeneous diseases in women worldwide which can be divided into several subtypes [1,2]. The treatment of triple-negative breast cancer (TNBC), a highly metastatic subtype, still remains challenging due to the lack of targeted therapy. An imbalance between cell proliferation and apoptosis promotes tumorigenesis. Chemotherapy, radiation therapy and immunotherapy, through inducing DNA damage and triggering apoptosis of cancer cells, are major treatment strategies for TNBC [5,6]. Antibody-drug conjugates (ADCs), which can allow exact targeting to tumour cell-surface proteins, are a new class of therapeutic agents for targeted cancer therapy [7]. Identification of differentially expressed cell-surface proteins in TNBC is deemed necessary for an effective and specific treatment
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