Toll-like receptors and breast cancer

Toll-like receptors (TLRs) are key receptors in innate immunity and inflammation and are expressed not only in innate immune cells but also in different cancer cells. Increasing evidences demonstrate that TLRs play an important role in the initiation and progression of cancer and metabolism. Currently we have limited therapeutic options to treat patients with advanced non-resectable, recurrent and metastatic breast cancer. An innate immunity-mediated anticancer immunotherapy, alone or in combination with other therapies, represents a promising novel approach. Indeed, some agonists and antagonists of TLRs have been utilized for anticancer immunotherapy in clinical trials. Thus, TLRs are not only involved in immune responses against pathogen infection but also play an important role in cancer immunity, and represent important targets for cancer immunotherapy. In this review, we discuss the recent progress about the role of TLRs in breast cancer development. Introduction Toll-like receptors (TLRs), a family of pattern-recognition receptors of innate immunity system, are Type I transmembrane receptors that protect the host against pathogen infections [1]. TLRs are defined by a cytoplasmic Toll/IL-1 receptor (TIR) domain and an extracellular leucine-rich repeat (LRR) domain. There are 10 human TLRs (TLR1–10), which can be classified into two subgroups according to their subcellular localization. TLR-3, 7, 8, and 9 are located mainly in intracellular endosome, whereas the others are distributed on the cell surface (Figure 1). TLRs recognized pathogen-associated molecular patterns (PAMPs), highly conserved components derived from bacteria, fungi, parasites and viruses, to prevent pathogens invading (Figure 1). Each TLR can recognize specific ligand, such as bacterial lipoproteins (TLR2), viral double-stranded RNA (TLR3), single-stranded RNA (TLR7) and CpGDNA (TLR9). Moreover, TLR2, in conjunction with TLR1 or TLR6, dramatically enhances its capacity of recognizing various bacterial components including lipopeptides, peptidoglycan and lipoproteins of gram-positive bacteria and mycoplasma. TLR4 effectively recognizes LPS, or endotoxin, expressing on Gram-negative bacteria with the help of CD14, MD-2 and the accessory protein LBP (LPS-binding protein), whereas TLR5 recognizes bacterial flagellin. TLR10 is so far an orphan receptor which is highly expressed in the human spleen and B cells. TLRs can also recognize endogenous danger-associated molecular patterns (DAMPs), which might be released in cancer development to activate inflammatory pathways [2]. For example, TLR4 plays an important role in the innate immune system; as a switch of the inflammatory response, TLR4 can maintain the body's normal defense function of foreign pathogens. However, its over expression will cause a series of inflammatory response, resulting in the damage of tissue and organs [3]. Lipopolysaccharide (LPS) which can activate TLR4 is a main toxic component in gram-negative bacterial cell wall. It has extensive biological effects on the body and it also can induce inflammation and infection [4]. Although the affinity of LPS with TLR4 is not high, CD14 may with the assist of MD-2 to joint with TLR4 binding and then can be recognized by the body of the innate immune system. Then causing downstream signal transduction pathways and stimulating the body to generate an immune response cause a strong inflammatory response and metabolic changes [5]. LPS is widely used for the activation of macrophage like cells and direct stimulation to lead to the infection. A large number of studies have also used LPS to induce nerve inflammation [4,6,7]. LPS is a potential stimulation of macrophages, monocytes, microglia and astrocytes, which can result in a variety of immune regulation and the release of pro-inflammatory cytokines [8]. TLRs and cancer Inflammation, as a new “hallmark of cancer”, has been implicated in cancer progression [9]. TLRs regulate tumor immune responses by controlling the suppressive function of regulatory T (Treg) cells and through innate immune responses mediated by other immune cells. TLR signaling plays an important role in tumor cell proliferation, local invasion, immune evasion, and distant metastasis. More recently, increasing evidence shows that engagement of TLRs can enhance cancer cell progression, induce evasion of immune surveillance, and induce tumor chemoresistance and metastasis. Surprisingly, the activation of some TLRs, however, can induce the tumor cell apoptosis, or even inhibition of tumor growth. Therefore, the role of TLRs in cancer development is complex. Correspondence to: Dekai Zhang, Center for Infectious and Inflammatory Disease, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX 77030, USA, Tel: +1 832 7661727, E-mail: [email protected] Huan Ren, Department of Immunology, Harbin Medical University, Harbin, China, Tel: +86-451-86674566, E-mail: [email protected]