Research progress of Claudin-low breast cancer

Abstract

Claudin-low breast cancer (CLBC) is a subgroup of breast cancer discovered at the molecular level in 2007. Claudin is one of the primary proteins that make up tight junctions, and it plays crucial roles in anti-inflammatory and antitumor responses as well as the maintenance of water and electrolyte balance. Decreased expression of claudin results in the disruption of tight junction structures and the activation of downstream signaling pathways, which can lead to tumor formation. The origin of Claudin-low breast cancer is still in dispute. Claudin-low breast cancer is characterized by low expression of Claudin3, 4, 7, E-cadherin, and HER2 and high expression of Vimentin, Snai 1/2, Twist 1/2, Zeb 1/2, and ALDH1, as well as stem cell characteristics. The clinical onset of claudin-low breast cancer is at menopause age, and its histological grade is higher. This subtype of breast cancer is more likely to spread to lymph nodes than other subtypes. Claudin-low breast cancer is frequently accompanied by increased invasiveness and a poor prognosis. According to a clinical retrospective analysis, claudin-low breast cancer can achieve low pathological complete remission. At present, although several therapeutic targets of claudin-low breast cancer have been identified, the effective treatment remains in basic research stages, and no animal studies or clinical trials have been designed. The origin, molecular biological characteristics, pathological characteristics, treatment, and prognosis of CLBC are extensively discussed in this article. This will contribute to a comprehensive understanding of CLBC and serve as the foundation for the individualization of breast cancer treatment.

Keywords: Claudin-low; breast cancer; epithelial-mesenchymal transformation; immunohistochemistry; mammary stem cells.

Figure 1

The structure of Claudin. The structure of Claudin mainly consists of four transmembrane structures (TM1, 2, 3, and 4), two extracellular loops, and one intracellular loop (ECL1, ECL2). The small extracellular loop contains the Clostridium perfringens enterotoxin-binding receptor (CPE), and the PDZ-interacting domain at the C-terminus of Claudin is capable of binding to Zonula occluden (Zos) to maintain cell homeostasis.

Figure 2

Claudin and Claudin low-expression carcinogenic signal pathway. (A) DOCK1/RRP1B/DNMT and TGF-β/SMAD2/DNMT induce Claudin low expression through methylation, and Claudin low expression through IL6/gp130/Stat3, Wnt/β-Catenin signal pathway; ERK/Sp1/CyclinD1 and ERK/IL8; PI3K/AKt/mTOR promotes EMT, migration and invasion of tumor. (B) Glycosylation of EPCAM was inhibited, and PI3K/AKt/mTOR was activated by combining with Claudin to promote EMT. (C) Claudin and Integrin β1 also inhibit the proliferation of tumor cells.