Molecular imaging plays an increasingly important role in the diagnosis and treatment of different malignancies. Radiolabeled probes enable the visualization of the primary tumor as well as the metastases and have been also employed in targeted therapy and theranostic approaches. With breast cancer being the most common malignancy in women worldwide it is of special interest to develop novel targeted treatments. However, tumor microenvironment and escape mechanisms often limit their therapeutic potential. Addressing tumor stroma associated targets provides a promising option to inhibit tumor growth and angiogenesis and to disrupt tumor tissue architecture. This review describes recent developments on radiolabeled probes used in diagnosis and treatment of breast cancer especially in triple negative type with the focus on potential targets offered by the tumor microenvironment, like tumor associated macrophages, cancer associated fibroblasts, and endothelial cells.

Recent studies proving prostate-specific membrane antigen (PSMA) expression on triple-negative breast cancer (TNBC) cells and adjacent endothelial cells suggest PSMA as a promising target for therapy of until now not-targetable cancer entities. In this study, PSMA and its isoform expression were analyzed in different TNBC cells, breast cancer stem cells (BCSCs), and tumor-associated endothelial cells. PSMA expression was detected in 91% of the investigated TNBC cell lines. The PSMA splice isoforms were predominantly found in the BCSCs. Tumor-conditioned media from two TNBC cell lines, BT-20 (high full-length PSMA expression, PSMAΔ18 expression) and Hs578T (low full-length PSMA expression, no isoform expression), showed significant pro-angiogenic effect with induction of tube formation in endothelial cells. All TNBC cell lines induced PSMA expression in human umbilical vein endothelial cells (HUVEC). Significant uptake of radiolabeled ligand [68Ga]Ga-PSMA was detected in BCSC1 (4.2%), corresponding to the high PSMA expression. Moreover, hypoxic conditions increased the uptake of radiolabeled ligand [177Lu]Lu-PSMA in MDA-MB-231 (0.4% vs. 3.4%, under hypoxia and normoxia, respectively) and MCF-10A (0.3% vs. 3.0%, under normoxia and hypoxia, respectively) significantly (p < 0.001). [177Lu]Lu-PSMA-induced apoptosis rates were highest in BT-20 and MDA-MB-231 associated endothelial cells. Together, these findings demonstrate the potential of PSMA-targeted therapy in TNBC.