Multidrug-resistant breast cancer: current perspectives

Abstract

Breast cancer is the most common cancer in women worldwide, and resistance to the current therapeutics, often concurrently, is an increasing clinical challenge. By understanding the molecular mechanisms behind multidrug-resistant breast cancer, new treatments may be developed. Here we review the recent advances in this understanding, emphasizing the common mechanisms underlying resistance to both targeted therapies, notably tamoxifen and trastuzumab, and traditional chemotherapies. We focus primarily on three molecular mechanisms, the phosphatidylinositide 3-kinase/Akt pathway, the role of microRNAs in gene silencing, and epigenetic alterations affecting gene expression, and discuss how these mechanisms can interact in multidrug resistance. The development of therapeutics targeting these mechanisms is also addressed.

Keywords: ER; HER2; PI3K/Akt; epigenetics; miRNA; triple negative.

Figure 1

Estrogen, HER2 signalling, and the PI3K/Akt pathway in drug-resistant breast cancer. Notes: ER can activate gene transcription by nuclear translocatin following ligand binding (1) or as a result of receptor phosphorylation in the absence of ligand (2). ERs may also be found associated with the plasma membrane in the presence of SRC and other adaptor proteins. Here, ligand binding triggers nongenomic effects via activation of signaling pathways, including the PI3K/Akt and the Ras/MAPK pathways (not shown) (3). These pathways are also activated by ligand binding to the GPR30 (4) and by growth factor binding to receptor tyrosine kinases, including HER2, inducing autophosphorylation and downstream signalling (5). The PI3K/Akt pathway (6) as indicated is a covergence point in the mechanisms implicated in drug resistance in the three types of breast cancer discussed here, as pathway hyperactivity frequently occurs with multiple downstream effects (7). Data from–,,,,,,,, Abbreviations: BAD, Bcl-2-associated death promoter; DMNTs, DNA methyltransfereases; E₂, estrogen; ER, estrogen receptor; GF, growth factor; GPR30, G-protein coupled receptor 30; GSK3B, glycogen synthase kinase 3 beta; HER2, human epidermal growth factor receptor 2; IGF-1R, insulin-like growth factor receptor 1; MAPK, mitogen-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; P-gp, P-glycoprotein; PI3K, phosphatidylinositide 3-kinase; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; SRC, steroid receptor coactivator.