Abstract
BackgroundCancer cell resistance to therapeutics can result from acquired or de novo-mediated factors. Here, we have utilised advanced breast cancer cell culture models to elucidate de novo doxorubicin resistance mechanisms.MethodsThe response of breast cancer cell lines (MCF-7 and MDA-MB-231) to doxorubicin was examined in an in vitro three-dimensional (3D) cell culture model. Cells were cultured with Matrigel™ enabling cellular arrangements into a 3D architecture in conjunction with cell-to-extracellular matrix (ECM) contact.ResultsBreast cancer cells cultured in a 3D ECM-based model demonstrated altered sensitivity to doxorubicin, when compared to those grown in corresponding two-dimensional (2D) monolayer culture conditions. Investigations into the factors triggering the observed doxorubicin resistance revealed that cell-to-ECM interactions played a pivotal role. This finding correlated with the up-regulation of pro-survival proteins in 3D ECM-containing cell culture conditions following exposure to doxorubicin. Inhibition of integrin signalling in combination with doxorubicin significantly reduced breast cancer cell viability. Furthermore, breast cancer cells grown in a 3D ECM-based model demonstrated a significantly reduced proliferation rate in comparison to cells cultured in 2D conditions.ConclusionCollectively, these novel findings reveal resistance mechanisms which may contribute to reduced doxorubicin sensitivity.
Highlights
Cancer cell resistance to therapeutics can result from acquired or de novo-mediated factors
Doxorubicin activity in 2D vs. 3D cell culture conditions A study was undertaken to evaluate doxorubicin resistance mechanisms exhibited by cells in a 3D extracellular matrix (ECM)-based breast cancer model
Doxorubicin was significantly (p ≤ 0.001) more potent against the breast cancer cells grown in 2D cultures in comparison to those cultured in a 3D ECM-based model (Table 1)
Summary
Cancer cell resistance to therapeutics can result from acquired or de novo-mediated factors. If the tumour is low grade, node-negative and estrogen-receptor positive, hormone therapy may be recommended, if the tumour is of high grade and/ or node-positive, chemotherapy is generally administered prior to targeted therapies depending on the hormonal/ ErBb2 status of the tumour [2]. Anthracyclines, such as doxorubicin and epirubicin; taxanes, including paclitaxel and docetaxel, along with fluorouracil and cyclophosphamide are the current therapeutics utilised for combination adjuvant breast cancer treatment [3]. De novo resistance can be mediated by environmental influences, such as tumour cell attachment to elements of the stroma, including the extracellular matrix (ECM) [8, 9]
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