Molecular characterization and targeted therapeutic approaches in breast cancer

Abstract

Despite the wide improvements in breast cancer (BC) detection and adjuvant treatment, BC is still responsible for approximately 40,000 deaths annually in the United States. Novel biomarkers are fundamental to assist clinicians in BC detection, risk stratification, disease subtyping, prediction of treatment response, and surveillance, allowing a more tailored approach to therapy in both primary and metastatic settings. In primary BC, the development of molecular profiling techniques has added prognostic and predictive information to conventional biomarkers--estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Moreover, the application of next-generation sequencing and reverse-phase protein microarray methods in the metastatic setting holds the promise to further advance toward a personalized management of cancer. The improvement in our understanding on BC biology associated with the study of the genomic aberrations characterizing the most common molecular subtypes allows us to explore new targets for drug development. Finally, the integration of cancer stem cell-targeted therapies and immune therapies in future combination regimens increases our chances to successfully treat a larger proportion of women with more aggressive and resistant metastatic disease. This article reviews the current state of novel biological markers for BC, the evidence to demonstrate their clinical validity and utility, and the implication for therapeutic targeting.

Figure 1

The PI3K/AKT/mTOR and the RAS/RAF/MEK/MAPK pathways. Phosphoinositide 3-kinase (PI3K) is a cytoplasmic lipid and protein kinase recruited to the membrane by activated growth factor receptors, including human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and insulin-like growth factor 1 (IGF-1R). PI3K phosphorylates the 3′-hydroxyl group of phosphoinositides to produce phoshatidylinositol-3,4,5-trisphosphate (PIP3), which is a second messenger that signals through AKT to activate several enzymes, kinases, and transcription factors, including mammalian target of rapamycin (mTOR). The RAS/RAF/MEK/MAPK pathway converges with the PI3K/AKT pathway and is now recognized as an alternative in mTOR activation. On the other hand, phosphatase and tensin homolog (PTEN) catalyzes PIP3 dephosphorylation, acting as a negative regulator of its activity. In parallel with activation of growth factor receptors, estrogens can activate nuclear estrogen receptors (ERs) (genomic pathway) or ERs on the membrane (non-genomic pathway). Membrane-associated ER binds to PI3K and activates molecules such as AKT and RAS, crosstalking with the growth factor signaling pathways. Erk1/2, extracellular-signal-regulated kinase 1/2; FOXO1, Forkhead box protein O1; MEK1/2, MAPK/Erk kinase 1/2; PIP, phosphatidylinositol phosphate; Raf, murine sarcoma viral oncogene homolog; Ras, rat sarcoma viral oncogene homolog; RHEB, Ras homolog enriched in brain; RTK, receptor tyrosine kinase; TSC1/2, tuberous sclerosis proteins 1 and 2.

Figure 2

Molecular pathways regulating breast cancer stem cells (CSCs). Akt represents a central hub in the Wnt/β-catenin and phosphoinositide 3-kinase (PI3K) signaling pathways. Upstream of Akt is the phosphatase and tensin homolog (PTEN) tumor suppressor. Loss of PTEN results in Akt activation and thus the activation of the Wnt/β-catenin pathway through the Akt-mediated phosphorylation of glycogen synthase kinase 3-beta (GSK3-β) and nuclear translocation of β-catenin. Through autocrine, juxtacrine, and paracrine mechanisms, secreted Hedgehog (Hh) interacts with the 12 trans-membrane Patched 1 (PTCH) receptor, de-repressing the 7 trans-membrane Smoothened (SMO) protein and allowing its translocation to the cilia. Activated SMO promotes a signaling cascade resulting in activation of the GLI transcription factors and thus in upregulation of genes that regulate cellular differentiation, proliferation, and survival. Four different Notch receptors (Notch 1, Notch 2, Notch 3, and Notch 4) interact with five ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1, and Jagged 2) expressed on neighboring cells. The interaction between ligand and the extracellular domain of Notch receptor triggers the cleavage by gamma-secretase and the release of the Notch intracellular domain (NICD), which translocates into the nucleus and associates with transcription factors regulating Notch target genes expression. The interaction between CXCR1/2 and interleukin (IL)-8 increases CSC self-renewal. HER2 regulates CSCs through the activation of the Wnt/β-catenin pathway, and loss of PTEN results in the downstream activation of the Wnt/β-catenin signaling. The activation of an inflammatory loop involving IL-6 and IL-8 has been shown to determine PTEN suppression and thus the resistance to HER2-targeting agents. IkB, kinase B inhibitor; p50, protein 50; Src, rous sarcoma oncogene cellular homolog; Stat3, signal transducer and activator of transcription 3.