Function and mechanism of action of the TRPV1 channel in the development of triple-negative breast cancer

Abstract

Transient receptor potential channel subfamily vanilloid 1 (TRPV1) is a member of the transient receptor potential family of nonselective cationic transmembrane channel proteins that are involved in the regulation of calcium homeostasis. It is expressed in various tumor types and has been implicated in the regulation of cancer growth, metastasis, apoptosis, and cancer-related pain. TRPV1 is highly expressed in triple-negative breast cancer (TNBC), and both its agonists and antagonists may exert anti-cancer effects. In this review, we provide an overview of the effect of TRPV1 on TNBC development and its influence on immunotherapy in an attempt to facilitate the development of future treatment strategies.

1. Introduction

In 2020, for the first time, the incidence and mortality rates of breast cancer in women increased significantly compared to those of women with lung cancer [1]. The latest statistics on the incidence and mortality of new cancers in China show that breast cancer is the most common tumor among females, and its mortality rate is on a continuous rise [2]. Breast cancer is classified into six subtypes based on molecular phenotype and gene expression, namely, luminal-A, luminal-B, HER-2 positive, basal-like (BLBC), normal-like [3] and claudin low [4]. Nearly 70%–80% of BLBC cases are triple-negative breast cancer (TNBC) [5]. Breast cancer is a highly heterogeneous disease with wide variations in its clinical management and prognosis. Existing treatment strategies for breast cancer include surgical resection, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy; however, none of these therapies have adequately addressed the problems of recurrence and metastasis, particularly in TNBC patients. Although PARP inhibitors are indicated for patients with breast cancer carrying BRCA mutations, they do not prolong the overall survival of these patients [6]. In recent years, the immune checkpoint inhibitor (ICI) atezolizumab (which targets PD-L1) in combination with albumin-paclitaxel has shown considerable efficacy against PD-L1-positive infiltrating lymphocytes in TNBC, thereby extending overall patient survival. However, the proportion of the population benefiting from this regimen is small [7], and this regimen was voluntarily withdrawn by Roche in 2021. The anti-PD-1 pembrolizumab combination chemotherapy regimen significantly improves survival to disease progression in patients with locally advanced breast cancer [8] and increases the rate of complete remission in patients receiving neoadjuvant treatment for early-stage TNBC [9]. Due to the lack of effective treatment options, the development of comprehensive therapies and specific therapeutic targets is urgently needed.

Transient receptor potential (TRP) channels are a family of cationic proteins. TRPV5 and TRPV6 are specific calcium channels, while the other members are nonselective [10]. Based on amino acid sequence homology, the mammalian TRP superfamily is divided into six subfamilies: the ankyrin (TRPA), canonical (TRPC), melastatin (TRPM), vanilloid (TRPV), mucolipin (TRPML), and polycytin (TRPP) subfamilies [11]. TRP channel activation is stimulated by various physical or chemical factors both inside and outside the cell, including diglycerides (DAG), inositol trisphosphate (IP3), pH, temperature changes, capsaicin, menthol, and mechanical stimuli [12]. TRP channels are widely distributed in various tissues and play important roles in the regulation of various cellular physiological and pathological functions [13]. Numerous studies have shown that TRP channel expression is important for tumor cell proliferation, migration, and angiogenesis [14–17]. For example, TRPV4, a mechanosensitive ion channel, decreases malignant progression by selectively inhibiting tumor endothelial cell proliferation to reduce tumor angiogenesis [16]. TRPV6 expression increases strongly in high-grade prostate cancer and promotes prostate cancer cell proliferation through a Ca2+/NFAT-dependent pathway [18,19]. Direct targeting or indirect blockade of TRPC5 can effectively overcome resistance to chemotherapy in colorectal cancer (CRC) cells [20]. TRPV6 and TRPM7 are associated with poor survival in patients with breast cancer [21,22]. The TRPC6 channel, which is essential for cell proliferation and cell cycle, is highly expressed in esophageal squamous cell carcinoma (ESCC) and renal cell carcinoma (RCC). TRPC6 channel inhibition induces G2/M phase arrest and suppresses cell proliferation. Therefore, TRPC6 may serve as a novel target for therapeutic intervention in ESCC and RCC [23–25]. Therefore, the TRP channel is considered a diagnostic and therapeutic target for cancer therapy and prognostic prediction.