Abstract
Compared to other breast cancers, triple-negative breast cancer (TNBC) usually affects younger patients, is larger in size, of higher grade and is biologically more aggressive. To date, conventional cytotoxic chemotherapy remains the only available treatment for TNBC because it lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2), and no alternative targetable molecules have been identified so far. The high biological and clinical heterogeneity adds a further challenge to TNBC management and requires the identification of new biomarkers to improve detection by imaging, thus allowing the specific treatment of each individual TNBC subtype. The Systematic Evolution of Ligands by EXponential enrichment (SELEX) technique holds great promise to the search for novel targetable biomarkers, and aptamer-based molecular approaches have the potential to overcome obstacles of current imaging and therapy modalities. In this review, we highlight recent advances in oligonucleotide aptamers used as imaging and/or therapeutic agents in TNBC, discussing the potential options to discover, image and hit new actionable targets in TNBC.
Highlights
Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of breast cancers, more frequently affects younger patients, is more prevalent in African American women and has frequently a poor prognosis [1]
By using the anti-epidermal growth factor receptor (EGFR) 2 -Fluoro-pyrimidine (2 F-Py)-RNA CL4 aptamer, previously validated as an efficacious targeting agent in GBM [61], Her2-positive breast cancer and NSCLC [41], we demonstrated a novel mechanism of action for this aptamer related with integrin αvβ3-EGFR interaction in TNBC [57]
We showed that, when ML TNBC MDA-MB-231 and BT-549 cells, expressing EGFR on their surface, are grown in 3D cultures or are injected in nude mice to form tumors, EGFR is associated with integrin αvβ3, one of the principal adhesion molecules expressed on cancer cells
Summary
Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of breast cancers, more frequently affects younger patients, is more prevalent in African American women and has frequently a poor prognosis [1]. According to the 2011 molecular classification by Lehmann et al [3], based on gene expression patterns, six distinct biological TNBC subtypes, including two basal-like (BL1, BL2), two mesenchymal-like (ML, MSL), one immunomodulatory (IM) and one luminal androgen receptor (LAR), were identified (Figure 1). The third cluster, characterized by high expression of an immune response gene module and lymphocyte infiltration, is associated with better outcome among patients with TNBC [11,12], while the fourth and last cluster, characterized by androgen receptor (AR), forkhead box protein A1 (FOXA1) and ERBB4 expression and signaling, share common gene profile with ER-positive breast cancer [13]. We highlight aptamer-based strategies to validate, as possible targets for therapeutic and/or imaging modalities, proteins with a recently proposed role in TNBC, including markers overexpressed on cancer cells, cancer stem cells (CSCs), stromal cell types within the TNBC microenvironment, as well as components of extracellular matrix (ECM)
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