Abstract
Studies carried out in the last decade have demonstrated that the members of the KCTD protein family play active roles in carcinogenesis. Very recently, it has been reported that KCTD15, a protein typically associated with other physio-pathological processes, is involved in medulloblastoma and leukemia. Starting with some preliminary indications that emerged from the analysis of online databases that suggested a possible overexpression of KCTD15 in breast cancer, in this study, we evaluated the expression levels of the protein in breast cancer cell lines and in patients and the effects of its silencing in the HER2+ cell model. The analysis of the KCTD15 levels indicates a significant overexpression of the protein in Luminal A and Luminal B breast cancer patients as well as in the related cell lines. The greatest level of over-expression of the protein was found in HER2+ patients and in the related SKBR3 cell line model system. The effects of KCTD15 silencing in terms of cell proliferation, cell cycle, and sensitivity to doxorubicin were evaluated in the SKBR3 cell line. Notably, the KCTD15 silencing in SKBR3 cells by CRISPR/CAS9 technology significantly attenuates their proliferation and cell cycle progression. Finally, we demonstrated that KCT15 silencing also sensitized SKBR3 cells to the cytotoxic agent doxorubicin, suggesting a possible role of the protein in anti HER2+ therapeutic strategies. Our results highlight a new possible player in HER2 breast cancer carcinogenesis, paving the way for its use in breast cancer diagnosis and therapy.
Highlights
Studies carried out in the last decade have clearly shown that the members of the protein family, known as KCTD (Potassium(K) Channel Tetramerization Domain containing proteins) are involved in diversified yet fundamental biological processes [1,2,3,4,5]
The role and the expression levels of KCTD15 in breast cancer were preliminarily evaluated by interrogating the Cancer Genome Atlas (TCGA) and normal Genotype-Tissue Expression (GTEx) databases using the GEPIA portal to possibly highlight differences in the mRNA expression level of KCTD15 in different breast cancer subtypes
We observed that KCTD15 is the only protein of the KCTD family that is over-expressed in a single breast cancer (BC) subtype, as all other KCTD proteins have no specific BC subtype expressions
Summary
Studies carried out in the last decade have clearly shown that the members of the protein family, known as KCTD (Potassium(K) Channel Tetramerization Domain containing proteins) are involved in diversified yet fundamental biological processes [1,2,3,4,5]. Surveys of literature data indicate that they are involved in obesity, genetic diseases, and cancer [5,6,7,8] In oncology, these proteins have been associated with medulloblastoma, breast cancer (BC), prostate adenocarcinoma, osteosarcoma, lung cancer, neuroendocrine tumors, and gastrointestinal stromal tumor [8,9,10]. The biochemical role(s) underlying this assortment of biological functions are yet to be uncovered, the observation that KCTD15 silencing-induced apoptosis and cell death in leukemia cell suggesting that it has a role in cellular homeostasis and proliferation prompted us an analysis of the KCTD15 expression levels in other oncological conditions In this scenario, we have recently shown that KCTD15 overexpression is associated with an activation of the NF-κB pathway, which likely occurs through an upregulation of IKK phosphorylation [19]. A connection between the KCTD15 and the NF-κB pathway has been detected in the breast cancer cell line SKBR3 [19]
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