Adiponectin is one of the most important adipocytokines secreted by adipocytes and is called a “guardian angel adipocytokine” owing to its unique biological functions. Adiponectin inversely correlates with body fat mass and visceral adiposity. Identified independently by four different research groups, adiponectin has multiple names; Acrp30, apM1, GBP28, and AdipoQ. Adiponectin mediates its biological functions via three known receptors, AdipoR1, AdipoR2, and T-cadherin, which are distributed throughout the body. Biological functions of adiponectin are multifold ranging from anti-diabetic, anti-atherogenic, anti-inflammatory to anti-cancer. Lower adiponectin levels have been associated with metabolic syndrome, type 2 diabetes, insulin resistance, cardiovascular diseases, and hypertension. A plethora of experimental evidence supports the role of obesity and increased adiposity in multiple cancers including breast, liver, pancreatic, prostrate, ovarian, and colorectal cancers. Obesity mediates its effect on cancer progression via dysregulation of adipocytokines including increased production of oncogenic adipokine leptin along with decreased production of adiponectin. Multiple studies have shown the protective role of adiponectin in obesity-associated diseases and cancer. Adiponectin modulates multiple signaling pathways to exert its physiological and protective functions. Many studies over the years have shown the beneficial effect of adiponectin in cancer regression and put forth various innovative ways to increase adiponectin levels.

Triple negative breast cancer (TNBC) is a molecularly heterogeneous disease whose incidence is disproportionately higher in African American (AA) women compared to European American (EA) women. Earlier onset, more advanced stage at diagnosis, and aggressive tumor phenotype are some of the characteristic features of TNBC in women with African ethnicity in comparison to EA women, denoting one of the most significant examples of racial disparity in oncology. It is still contentious whether health disparities result in aggressive behavior of TNBC in AA women or it is indeed a molecularly distinct disease. Given the “gaps-in-knowledge” surrounding racial disparity in TNBC, this review discusses various socioeconomic factors and the genetic predispositions contributing to poor prognosis of TNBC in AA women. While socioeconomic factors may contribute to poorer survival, multiple preclinical and clinical studies suggest inherent genetic risk factors and aberrant activation of oncogenic pathways in AA TNBC. Additionally, AA women are more likely to be obese and obesity is known to drive a molecular circuitry resulting in aggressive tumor progression indicating a potential obesity-TNBC axis at work in AA women. Given the multifactorial nature of AA TNBC, a transdisciplinary approach may help bridge the disparity that exists between AA and EA TNBC.

Metastatic progression and tumor recurrence pertaining to TNBC are certainly the leading cause of breast cancer-related mortality; however, the mechanisms underlying TNBC chemoresistance, metastasis, and tumor relapse remain somewhat ambiguous. TNBCs show 77% of the overall 4-year survival rate compared to other breast cancer subtypes (82.7 to 92.5%). TNBC is the most aggressive subtype of breast cancer, with chemotherapy being the major approved treatment strategy. Activation of ABC transporters and DNA damage response genes alongside an enrichment of cancer stem cells and metabolic reprogramming upon chemotherapy contribute to the selection of chemoresistant cells, majorly responsible for the failure of anti-chemotherapeutic regime. These selected chemoresistant cells further lead to distant metastasis and tumor relapse. The present review discusses the approved standard of care and targetable molecular mechanisms in chemoresistance and provides a comprehensive update regarding the recent advances in TNBC management.

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

Racial disparities are most accentuated among Black women as their lifetime risk of breast cancer incidence is lower than white and Asian women but their breast cancer related mortality is the highest among all races. Black women are more likely to develop triple-negative breast cancer at a younger age and harbor more aggressive tumors. In addition to tumor-centric alterations, tumor growth is also influenced by multiple other tumor microenvironment-related features, including resident immune cells and microbiota. Hence, in this study, we conduct concurrent genomic and metagenomic analyses, and uncover distinctive intratumoral microbial community compositions and tumor immune microenvironment-related traits in breast tumors from Asian, Black and white women. Interestingly, unique racially associated genomic nodes are found in the breast tumors from Asian, Black and white women. Examination of the cellular heterogeneity show differential enrichment of 11 out of 64 immune and stroma cell types in the breast tumors from different racial groups. In terms of microbial diversity, significant differences are revealed in alpha and beta-diversity measures. Intriguingly, potential race-specific microbial biomarkers of breast cancer are identified which significantly correlate with genes involved with tumor aggressiveness, angiogenesis, tumor cell migration and metastasis as well as oncogenic pathways-GLI and Notch. Investigating the metabolic features of intratumoral microbes, we find a significant differential enrichment of environmental information processing pathways, oncogenic pathways, and lipid metabolism pathways. Concomitantly investigating tumor-centric, tumor immune microenvironment-related and microbial alterations, our study provides a comprehensive understanding of racial disparities in breast cancer and warrants further exploration.