CD73 (ecto-5'-nucleotidase) function in breast cancer progression and promotion, and its assessment as a therapeutic target

Breast cancer, the most common cancer type in women, is still considered a clinical challenge due to its high level of recurrence and resulting morbidity. Therefore, new therapies need to be considered. However, breast cancer is a complex disease, which needs to be stratified, before the decision on the patient's treatment, based not only on clinical information but often also on the expression of specific molecular biomarkers, estrogen, progesterone, and HER2 receptors. Such heterogeneity introduces great variability in the treatment outcome and new, potential therapies should take that under consideration.One of the emerging therapeutic targets in cancer is CD73 (ecto-5'-nucleotidase), a cell surface protein, with a dual activity as a cell adhesion molecule and an enzyme hydrolyzing 5'-AMP to extracellular adenosine. Its inhibition or knockout in pre-clinical, animal models was demonstrated to inhibit the growth of many tumor types as well their metastatic spread. In clinical patients, high CD73 expression was demonstrated to correlate with poor overall survival and a worse outcome for many cancer types. However, for breast cancer, the prognostic implication of CD73 expression was demonstrated to be controversial in clinical patients, and its dependence on other clinical indexes, e.g., cancer subtype, was suggested. Therefore, in depth analysis of CD73's role in breast cancer is needed. First, to analyze CD73's multi-faceted function in breast cancer and its potential correlation with a specific tumor stratification. Second, to find a reason for a lack of consistency between the data obtained from pre-clinical models and from clinical samples to assess, which functions of CD73 in breast cancer development and progression could possibly limit its usefulness as a therapeutic target.However, for the successful translation of new data from mouse model to the clinic, a pre-clinical the model should reflect similar heterogeneity and developmental pathway as human disease. This was obtained using two-stage chemical carcinogenesis in an animal model to stimulate in the mammary gland all three main steps of cancer development: initiation, promotion, and progression. Subcutaneous administration of medroxyprogesterone acetate (MPA), a synthetic analog of progesterone, primes mammary gland for carcinogenesis by DMBA (7,12-dimethylbenz[a]anthracene). Tumors arising from combined MPA and DMBA treatment give rise to breast cancer tumors with different stratification.In this project the use of the transgenic model with CD73 knockout for carcinogenesis allowed us to extensively analyze CD73's role in changes present in the mammary gland at both breast cancer's initiation and progression stages as compared to non-modified mice. The changes in tumor's growth rate and burden, latency, incidence or multiplicity, as well as changes in neoangiogenesis, tumor infiltration by immune cells, changes in EMT and stem cells, and general changes in the immune system, were analyzed and correlated with cancer histological type and molecular stratification.