Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

Abstract

Breast cancer is the most frequently diagnosed cancer and the principal cause of mortality by malignancy in women and represents a main problem for public health worldwide. Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine whose expression is increased in a variety of cancers. In particular, in breast cancer it correlates with augmented tumor cell proliferation, higher malignancy grade, increased occurrence of metastasis and general poor prognosis for the patient. These characteristics highlight TNFα as an attractive therapeutic target, and consequently, the study of soluble and transmembrane TNFα effects and its receptors in breast cancer is an area of active research. In this review we summarize the recent findings on TNFα participation in luminal, HER2-positive and triple negative breast cancer progression and metastasis. Also, we describe TNFα role in immune response against tumors and in chemotherapy, hormone therapy, HER2-targeted therapy and anti-immune checkpoint therapy resistance in breast cancer. Furthermore, we discuss the use of TNFα blocking strategies as potential therapies and their clinical relevance for breast cancer. These TNFα blocking agents have long been used in the clinical setting to treat inflammatory and autoimmune diseases. TNFα blockade can be achieved by monoclonal antibodies (such as infliximab, adalimumab, etc.), fusion proteins (etanercept) and dominant negative proteins (INB03). Here we address the different effects of each compound and also analyze the use of potential biomarkers in the selection of patients who would benefit from a combination of TNFα blocking agents with HER2-targeted treatments to prevent or overcome therapy resistance in breast cancer.

Keywords: TNFα; breast cancer; mucin 4; resistance; targeted-therapy.

Figure 1

TNFα enhances luminal breast cancer cell proliferation by aromatase upregulation. TNFα is produced by adipose cells, TAM or tumor cells itself, and induces the expression of aromatase. This enzyme increases estradiol synthesis which binds to ER that, in turn, promotes luminal cancer cell proliferation. IL-10 and docetaxel and paclitaxel inhibit aromatase synthesis by reducing TNFα signaling. sTNFα, soluble TNFα; TAM, tumor-associated macrophages; E2, estradiol; ER, estrogen receptor.

Figure 2

TNFα signaling in luminal breast cancer cells. TNFα binds to TNFR1 and induces the activation of PI3K/Akt, p42/p44MAPK and JNK, while its binding to TNFR2 mainly induces p42/p44MAPK activation. PI3K/Akt and JNK then activates NF-κB that promotes the transcription of cyclin D1 and the consequent cell proliferation. In addition, NF-κB also induces the expression of TNFα, establishing a positive feed-back. E2 binds to ER and also promotes luminal cancer cell proliferation through cyclin D1 upregulation by tethering NF-κB and enhances its activity. sTNFα, soluble TNFα; TNFR1, TNFα receptor 1; TNFR2, TNFα receptor 2; E2, estradiol; ER, estrogen receptor.

Figure 3

TNFα promotes proliferation and EMT in TNBC cells. TNFα, acting mainly through TNFR1, induces NF-κB and c-Jun activation, which inhibits apoptosis and enhance the transcription of survival factors (i.e., Bcl-2), the expression of inflammatory cell recruitment chemokines (i.e., CCL2) and promotes transcription of factors related to EMT (i.e., increases Ninj1, MMP2, and MMP9 transcription and decreases E-cadherin transcription). sTNFα, soluble TNFα; TNFR1, TNFα receptor 1; MMP, metalloproteinase; EMT, epithelial-mesenchymal transition.

Figure 4

TNFα transactivates HER2 receptor and induces cell proliferation. TNFα, acting mainly through TNFR1, activates p42/p44MAPK, JNK, and c-Src. This last kinase phosphorylates HER2 and induces HER2/HER3 heterodimer formation and activation of PI3K/Akt pathway. JNK and Akt activates NF-κB that induces transcription of cyclin D1 and Bcl-xL. TNFα, soluble TNFα; TNFR1, TNFα receptor 1.

Figure 5

sTNFα blockade overcomes trastuzumab resistance and favors a less immunosuppressive tumor microenvironment. (A) sTNFα induces the upregulation of the membrane glycoprotein MUC4 in HER2-positive breast tumors. MUC4 masks trastuzumab epitope on the HER2 molecule, impairing its binding and ADCC exerted by NK cells, generating resistance to the antibody. This resistance is accompanied by an immunosuppressive tumor microenvironment with an increased infiltration of MDSCs and macrophage polarization to the M2 subtype. (B) sTNFα blockade with a dominant negative protein (DN-sTNFα) downregulates MUC4 expression, enabling trastuzumab to induce NK cell ADCC. This antitumor innate immune response generates a less immunosuppressive tumor microenvironment, decreasing MDSCs infiltration, and increasing macrophage polarization to the M1 subtype. (C) NK cell activation and degranulation induced by trastuzumab treatment kills tumor cells through ADCC. sTNFα, soluble TNFα; TNFR1, TNFα receptor 1; MUC4, mucin 4; MDSC, myeloid-derived suppressor cells; Mϕ, macrophages.