Transcriptional Profiling of Tumorspheres Reveals TRPM4 as a Novel Stemness Regulator in Breast Cancer

Abstract

Cancer stem cells (CSCs) have been implicated in the development of chemoresistance, tumor recurrence and metastasis in breast cancer, thus emerging as a promising target for novel therapies. To identify novel stemness regulators that could potentially be targeted in luminal ER+ tumors, we performed RNA-sequencing (RNA-seq) in MCF-7 adherent monolayer cells and tumorspheres enriched in breast CSCs (bCSCs). We identified 1421 differentially expressed genes (DEGs), with 923 of them being upregulated and 498 downregulated in tumorspheres. Gene ontology and pathway enrichment analyses revealed that distinct gene networks underlie the biology of the two cell systems. We selected the transient receptor potential cation channel subfamily M member 4 (TRPM4) gene that had not been associated with cancer stemness before for further investigation. We confirmed that TRPM4 was overexpressed in tumorspheres and showed that its knock-down affected the stemness properties of bCSCs in vitro. TRPM4 inhibition revealed potential anti-tumor effects by directly targeting the bCSC subpopulation. We suggest that TRPM4 plays a key role in stemness mediation, and its inhibition may represent a novel therapeutic modality against bCSCs contributing in the improvement of breast cancer treatments.

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“…Accordingly, we selected two specific TRPV2 inhibitors—namely, tranilast and SKF-96365 (as stated by literature) [ 41 , 42 ]—and the rather general TRP inhibitor 2-APB. Finally, the TRPM4 blocker 9-phenantrol was also used due to a recently identified role of TRPM4 in breast cancer [ 43 ].…”

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“…Moreover, TRPM4 is responsible for stemness mediation in breast cancer. It is overexpressed in breast cancer tumor-spheres and its inhibition displays anti-tumor effects by directly targeting cancer stem cells [61]. Finally, it has also been classified as a cancer driver gene in androgen-independent prostate cancer where it regulates the EMT, which is fundamental for cancer cell migration and invasion.…”

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“…TRPM4 channel activity is greatly enhanced by ATP depletion and increases in the intracellular Ca 2+ level; both changes are associated with hypoxia, a condition commonly present in cancer cells. Moreover, TRPM4 can play a key role in stemness mediation [208]. Cancer stem cells play roles in chemoresistance, tumor recurrence, and metastasis in breast cancer.…”

“…Cancer stem cells play roles in chemoresistance, tumor recurrence, and metastasis in breast cancer. TRPM4 inhibition reduced stemness properties of breast cancer stem cells in vitro, therefore TRPM4 can be a novel therapeutic target [208].…”