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.