Abstract
As breast cancer cells often develop chemoresistance, better therapeutic options are in search to circumvent it. Here we demonstrate that human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer cells resist docetaxel-induced cytotoxicity by upregulating HER-2 and its activity downstream, through Akt and mitogen-activated protein kinase (MAPK) pathways. We observed that introducing resveratrol as a chemosensitizer in docetaxel chemotherapy blocks upregulation and activation of HER-2 in addition to blocking downstream signaling pathways such as Akt. Resveratrol and docetaxel combination results in the synergistic induction of cell death in HER-2-overexpressing SK-BR-3 cells, whereas introduction of wild-type HER-2 in MDA-MD-231 cells increased the resistance to docetaxel. Dominant-negative HER-2 sensitizes SK-BR-3 cells to docetaxel. Our study identified a new synergistic therapeutic combination that targets HER-2-induced breast cancer resistance and might help to overcome therapeutic resistance during breast cancer therapy. The synergism of docetaxel and resveratrol was maximum in SK-BR-3, which is unique among the cell lines studied, due to its high expression status of HER-2, a receptor known to dictate the signaling environment of breast cancer cells. Docetaxel could further induce HER-2 activity in these cells, which was downregulated on resveratrol treatment. Transfection of DN-HER-2 in SK-BR-3 cells inhibits the synergism as the transfection itself sensitizes these cells to docetaxel, leaving no role for resveratrol, whereas ectopic expression of HER-2 introduces the synergism in MDA-MB-231, the triple-negative cell line, in which the synergism was minimum, attesting the crucial role of HER-2 in suppressing the sensitivity to docetaxel. Single-agent docetaxel induced HER-2-mediated resistance to cell death, which was blocked by resveratrol. Resveratrol also downregulated docetaxel-induced activation of MAPK and Akt, survival signaling pathways downstream of HER-2. In short, this study, for the first time, establishes the role of HER-2–Akt signaling axis in regulating the synergistic effect of docetaxel and resveratrol in breast cancer cells overexpressing HER-2.
Highlights
Being the most frequently diagnosed female cancer worldwide, breast cancer is always a mystifying puzzle, owing to its highly heterogeneous and complex nature
To evaluate the role of human epidermal growth factor receptor-2 (HER-2) in regulating the synergism, HER-2 signaling was inhibited in SK-BR-3 cells by transfecting DN-HER-2 [K753M] and overexpressed in MDA-MB-231, the triple-negative cell line, by transfecting WT-HER-2, and the synergism was evaluated in these cells and compared with that of vector-transfected cells
The synergism was completely abolished in DN-HER-2transfected cells, whereas it was persistent in vector-transfected cells (Figure 3d), as the inactivation of HER-2 itself sensitizes the cells to docetaxel and there is no significant role for resveratrol as a chemosensitizer
Summary
Being the most frequently diagnosed female cancer worldwide, breast cancer is always a mystifying puzzle, owing to its highly heterogeneous and complex nature. In 20–25% of invasive breast cancers, HER-2 gene is either overexpressed or amplified.[4] As an epidermal growth factor receptor (EGFR), HER-2 is not known to bind with any known ligands but can heterodimerize with other related EGFR family members. By doing so, it could recruit various adaptor proteins, which in turn lead to the activation of multiple signal transduction cascades including RAF–MEK–ERK and PI3K/AKT/mTOR pathways.[5] All these signaling events activated on HER-2 overexpression provide a pro-survival environment in breast cancer cells leading to chemotherapeutic resistance. There are ample evidence regarding the activation of survival signals including the prominent kinase networks such as mitogen-activated protein kinase (MAPK) and PI3K/Akt or the transcription factor such as nuclear factor-κB (NF-κB) and AP-1 in response to docetaxel treatment, which in turn could create a cellular pro-survival environment leading to apoptosis resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
