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TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway

1
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
2
State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China
3
Key Laboratory for Regenerative Medicine, Ministry of Education, The Chinese University of Hong Kong, Hong Kong, China
4
Centre for Novel Biomaterials, The Chinese University of Hong Kong, Hong Kong, China
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(4), 558; https://doi.org/10.3390/cancers11040558
Received: 1 March 2019 / Revised: 13 April 2019 / Accepted: 16 April 2019 / Published: 18 April 2019
(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)
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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. View Full-Text
Keywords: TRPC3; calcium influx; triple-negative breast cancer; apoptosis resistance; RASA4; MAPK pathway TRPC3; calcium influx; triple-negative breast cancer; apoptosis resistance; RASA4; MAPK pathway
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Wang, Y.; Qi, Y.-X.; Qi, Z.; Tsang, S.-Y. TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway. Cancers 2019, 11, 558.

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