Official websites use. Share sensitive information only on official, secure websites. Corresponding author. However, its role in the tumorigenesis process remains mostly obscure. We aimed to demonstrate CD73's role in breast cancer BC tumorigenesis through metabolic rewiring of fatty acid metabolism, a process recently indicated to be regulated by BC major prognostic markers, hormone receptors HR for estrogen ER , and progesterone PR.
Our results support combining therapy targeting the CDadenosine axis and tumor lipidome against HR-negative tumors, especially at their earliest developmental stage. In preclinical research, its depletion through genetic alterations or inhibition decreased the tumor growth and metastasis of many cancer types, including BC [ 4 , 5 ]. Through extracellular adenosine-regulated purinergic signaling, CD73 mediates several tissue-protective mechanisms, both physiological and pathological.
Its expression and activity are upregulated as a part of an adaptive response to hypoxia or inflammation. In syngeneic or xenotransplant mouse models, CD73 was shown to favor the progression of neoplastic disease mainly through the generation of an immunosuppressed niche, stimulation of angiogenesis, cancer cell proliferation, and epithelial-to-mesenchymal transition [ 5 , 6 ].
Its depletion also reduced tumor incidence in the murine model of 3-methyl-cholanthrene-induced fibrosarcoma and delayed the onset of prostate cancer in TRAMP transgenic mice in correlation with its immunomodulatory activity [ 7 ]. Furthermore, the CDadenosine axis plays dual and opposite action on BC proliferation depending on the engagement of different adenosine receptors AdoR. Estrogen, through stimulation of cellular proliferation and due to its genotoxic metabolites [ 9 ], as well as progesterone receptor signaling [ 10 , 11 ] are indicated as critical mediators in mammary gland carcinogenesis.
Both ER and PR also seem to have a role in the regulation of the balance between de novo FA synthesis and their oxidation FAO with differential expression of lipid metabolism-related genes depending on the BC subtype [ 12 , 13 ].
