Deconstructing breast cancer cell biology and the mechanisms of multidrug resistance |
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| Authors: | Mafalda Videira Rita Leones Reis Maria Alexandra Brito |
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| Affiliation: | 1. Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal;2. Department of Galenic Pharmacy and Pharmaceutical Technology, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal;3. Department of Biochemistry and Human Biology, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal |
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| Abstract: | Cancer complexity constantly challenges the way that clinicians manage breast cancer therapy. Tumor heterogeneity and intratumoral stroma characteristics allow cells with different phenotypes and deregulated apoptotic, proliferative and migration abilities to co-exist contributing to a disappointing therapeutic response. While new approaches are being associated with conventional chemotherapy, such as hormonal therapy or target monoclonal antibodies, recurrence and metastasization are still observed. Membrane transporters are the cell's first line of contact with anticancer drugs having a major role in multidrug resistance events. This structural-based activity enables the cell to be drug-resistant by decreasing drug intracellular concentration through an efflux-transport mechanism, mainly associated with overexpression of ATP-binding cassette (ABC) proteins. This review focuses on some of the important structural and biological properties of the malignant cell and tumor microenvironment, addressing the role of the membrane ABC transporters in therapeutic outcomes, and highlighting related molecular pathways that may represent meaningful target therapies. |
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| Keywords: | ABC, ATP-binding cassette BC, breast cancer BCRP, breast cancer resistance protein CAFs, cancer-associated fibroblasts CSC, cancer stem cells ECM, extracellular matrix EGF, epidermal growth factor EMT, epithelial-mesenchymal transition ER, estrogen receptor HER2, human epidermal growth factor receptor 2 HIF-1α, hypoxia inducible factor-1α MDR, multidrug resistance HGF, hepatocyte growth factor mTOR, mammalian target of rapamycin LOX, lysyl oxidase MAPK, mitogen-activated protein kinase MMPs, matrix metalloproteinases MRP, multidrug resistance-associated protein NBD, nucleotide binding domain NF-kB, nuclear factor kappa B NOS, nitric oxide synthase P-gp, P-glycoprotein PI3K, phosphoinositide 3-kinase PR, progesterone receptor TAMs, tumor associated macrophages TGF-β, transforming growth factor-β TMDs, transmembrane domains TNF-α, tumor necrosis factor-α VEGF, vascular endothelial growth factor |
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