Altered Adipokine Expression in Tumor Microenvironment Promotes Development of Triple Negative Breast Cancer

Abstract

Obesity is a remarkably important factor for breast carcinogenesis and aggressiveness. The implication of increased BMI in triple negative breast cancer (TNBC) development is also well established. A malignancy-promoting role of the adipose tissue has been supposed, where the adipocytes that constitute the majority of stromal cells release pro-inflammatory cytokines and growth factors. Alterations in adipokines and their receptors play significant roles in breast cancer initiation, progression, metastasis, and drug response. Classic adipokines, such as leptin, adiponectin, and resistin, have been extensively studied in breast cancer and connected with breast cancer risk and progression. Notably, new molecules are constantly being discovered and the list is continuously growing. Additionally, substantial progress has been made concerning their differential expression in association with clinical and pathological parameters of tumors and the prognostic and predictive value of their dysregulation in breast cancer carcinogenesis. However, evidence regarding the mechanisms by which adipose tissue is involved in the development of TNBC is lacking. In the present article we comment on current data on the suggested involvement of these mediators in breast cancer development and progression, with particular emphasis on TNBC, to draw attention to the design of novel targeted therapies and biomarkers.

Exploring GZMK as a prognostic marker and predictor of immunotherapy response in breast cancer: unveiling novel insights into treatment outcomes

“…In studies related to GZMB, it was observed that in the PD-L1-positive group, Kaplan-Meier analysis revealed better recurrence-free survival (RFS) and OS in triple-negative breast cancer (TNBC) patients with high expression of GZMB (defined as ≥ 1% tumor-infiltrating lymphocytes (TILs) positive). Both RFS and OS were significantly prolonged in patients with high GZMB expression (RFS: P = 0.0220, OS: P = 0.0254) (Mizoguchi et al 2023). Multivariable Cox analysis also indicated better OS in patients with high expressions of PD-L1 and GZMB (hazard ratio: 0.25 (95% CI: 0.07-0.88), P = 0.03), suggesting that GZMB is a useful prognostic biomarker for PD-L1-positive TNBC patients (Mizoguchi et al 2023).…”

“…Both RFS and OS were significantly prolonged in patients with high GZMB expression (RFS: P = 0.0220, OS: P = 0.0254) (Mizoguchi et al 2023). Multivariable Cox analysis also indicated better OS in patients with high expressions of PD-L1 and GZMB (hazard ratio: 0.25 (95% CI: 0.07-0.88), P = 0.03), suggesting that GZMB is a useful prognostic biomarker for PD-L1-positive TNBC patients (Mizoguchi et al 2023). Additionally, a study found that high expression of GZMK in advanced melanoma significantly improved patients' PFS and OS (PFS: P = 0.04, OS: P = 0.01) (Wu et al 2021b).…”

Overcoming the Challenges of Phytochemicals in Triple Negative Breast Cancer Therapy: The Path Forward

“…These biochemical alterations have been linked to an increased risk of getting cancer, particularly TNBC. Furthermore, adipokines, which are signaling molecules generated by fat cells, may have a role in raising the risk of TNBC [ 34 ]. Hormonal treatment, which includes hormone replacement therapy and oral contraceptives, is another concern [ 7 , 35 ].…”

Role of Leptin and Adiponectin in Carcinogenesis

“…Leptin and adiponectin interact with the tumor microenvironment (TME) [3,15]. Crosstalk between adipokines and TME components leads to the epithelial-mesenchymal transition (EMT) activation program, which is critical for tumor malignancy and metastasis [12].…”