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.
Highlights
Breast cancer is the most prevalent cancer worldwide, with 2.3 million women having been diagnosed with the disease and 685,000 patients having died of it in 2020 [1]
Our results suggest that TRPM4 is a novel breast cancer stem cells (bCSCs)-regulator, and its targeting may lead to a significant reduction of this aggressive subpopulation and may enhance therapeutic results in breast cancer
FACS analysis of the inhibitor-treated mammospheres showed an approximately 50% decrease in the CD44+ CD24−/low Cancer stem cells (CSCs)-subpopulation compared to control mammospheres (Figure 6C,D). These results strongly suggest that TRPM4 inhibition diminishes the stemness potential of bCSCs and targets directly this subpopulation in MCF-7 mammospheres
Summary
Breast cancer is the most prevalent cancer worldwide, with 2.3 million women having been diagnosed with the disease and 685,000 patients having died of it in 2020 [1]. Conventional chemotherapy is still at the forefront of treatment regimens, being effective in inciting tumor remission, yet a considerable fraction of patients ends up developing resistance and suffering relapse overtime [2] This occurs even in the least aggressive subtype of BC, the luminal ER+ , which is treated with chemotherapy in advanced cases, and has a good prognosis in the initial 5 years after diagnosis, but has an increased chronic annual risk of recurrence thereafter [3]. A possible explanation to account for this observation is based on the existence of rare tumor subpopulations with intrinsic resistance that survive treatment and drive tumor regrowth leading to patient relapse Such tumor cells possess oftentimes stem-like characteristics, such as self-renewal and the capacity for differentiation, and are referred to as breast cancer stem cells (bCSCs).
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