Focus on Triple-Negative Breast Cancer: Potassium Channel Expression and Clinical Correlates

Abstract

Despite improvements in early diagnosis and treatment, breast cancer is still a major health problem worldwide. Among breast cancer subtypes, the most challenging and harder to treat is represented by triple-negative molecular subtype. Due to its intrinsic features this subtype cannot be treated neither with hormonal therapy (since it does not express estrogen or progesterone receptors) nor with epidermal growth factor receptor 2 (HER2) inhibitors (as it does not express high levels of this protein). For these reasons, the standard of care for these patients is represented by a combination of surgery, radiation therapy and chemotherapy. In this scenario, searching for novel biomarkers that might help both in diagnosis and therapy is mandatory. In the last years, it was shown that different families of potassium channels are overexpressed in primary breast cancers. The altered ion channel expression may be useful for diagnostic and therapeutic purposes due to some peculiar characteristics of this class of molecules. Ion channels are defined as pore-forming transmembrane proteins regulating passive ion fluxes in the cells. Ion channels represent good potential markers since, being localized at the plasma membrane level, their detection and block with specific drugs and antibodies might be fast and tunable. This review focuses on triple-negative breast cancers and recapitulates the current knowledge about potassium channels' clinical relevance and their potential use in the clinical setting, for triple-negative breast cancer diagnosis and therapy.

A Multidisciplinary Approach Establishes a Link between Transglutaminase 2 and the Kv10.1 Voltage-Dependent K+ Channel in Breast Cancer

“…These effects take place following the interaction between TG2 and another voltage-dependent channel, Kv7, modulated by the G-protein function of TG2, as demonstrated using the specific inhibitor LDN 27129 [44]. However, Kv7 channels do not seem to have any important role in eliciting the membrane current of BC cells [40], whereas Kv10.1 is involved [75]. The expression of the Kv10.1 channel, as well as that of Orai1, which sustains Ca 2+ influx, depends on the activation of the discoidin domain receptor 1 pathway, which is mediated by collagen type I and activated via ERK1/2 [76,77].…”

“…Overall, K + channels have a leading role and represent good candidates as markers. They are easily druggable, owing to their position on the cell membrane [40]. The voltage-dependent Kv10.1 channel (also named ether à-go-go-1, Eag1) has been indicated as a good target for therapy of most human tumors [41], despite its similar structure to the Kv11.1 channel (human ether-à-go-go-related gene, hERG), which is relevant for cardiac physiology.…”

Micronutrient Status and Breast Cancer: A Narrative Review

“…There have been reports that the potassium ions that are dependent on their level might play an important role in breast cancer onset. Lastraioli E. reported on 1.3 voltage-gated potassium ion channels (KV channels), the overexpression of which could correlate with the progression of breast cancer [248]. It has been demonstrated that the KV 1.3 channels are linked to a bad prognosis in patients with breast cancer.…”

Potassium Channels, Glucose Metabolism and Glycosylation in Cancer Cells

“…Other potassium channels, such as the voltage-gated potassium channels, are highly expressed in ductal pancreas adenocarcinoma (PDAC), and their blockade could be a useful therapeutic strategy to be added to conventional therapy [218]. Also in breast cancer, in particular the triple-negative type, it has been seen that the expression of potassium channels determines increased in vitro invasion, tumor growth in vivo, and metastases, so it is interesting to reposition already approved potassium channel-blocking drugs for the therapy of this type of particularly aggressive cancer [219,220]. In breast cancer, the expression of potassium channel subfamily K member 6 (K 2P 6.1) is also increased, which enhances the proliferation, invasion, and migratory capacity of cancer cells.…”