Abstract
The resistance of cancer cells to chemotherapeutic agents represents the main problem in cancer treatment. Despite intensive research, mechanisms of resistance have not yet been fully elucidated. Six1 signaling has an important role in the expansion of progenitor cell populations during early embryogenesis. Six1 gene overexpression has been strongly associated with aggressiveness, invasiveness, and poor prognosis of different cancers. In this study, we investigated the role of Six1 signaling in resistance of MCF-7 breast cancer cells to taxanes. We first established in vitro paclitaxel-resistant MCF-7 breast cancer cells. Morphological modifications in paclitaxel-resistant cells were examined via light microscopic images and fluorescence-activated cell sorting analysis. Applying quantitative real-time polymerase chain reaction, we measured Six1, B-cell lymphoma/leukemia(BCL-2), BAX, and P53 mRNA expression levels in both non-resistant and resistant cells. Resistant cells were developed from the parent MCF-7 cells by applying increasing concentrations of paclitaxel up to 64 nM. The inhibitory concentration 50% value in resistant cells increased from 3.5 ± 0.03 to 511 ± 10.22 nM (p = 0.015). In paclitaxel-resistant cells, there was a significant increase in Six1 and BCL-2 mRNA levels (p = 0.0007) with a marked decrease in pro-apoptotic Bax mRNA expression level (p = 0.03); however, there was no significant change in P53 expression (p = 0.025). Our results suggest that identifying cancer patients with high Six1 expression and then inhibition of Six1 signaling can improve the efficiency of chemotherapeutic agents in the induction of apoptosis.
Highlights
Breast cancer is the most frequent cancer among women aged between 50 and 70
Sineoculishomeobox homolog 1 (Six1) mRNA is over expressed in pancreatic cancer which is associated with the advanced tumor stage
After determination of cytotoxicity in resistant and non-resistant cells, the effects of high concentrations of paclitaxel were examined on resistant-MCF-7 cells to evaluate mRNA expression levels of Six1 and P53 [12]
Summary
Breast cancer is the most frequent cancer among women aged between 50 and 70. It affects one in eight women on average. Paclitaxel is one of the first-line treatments for breast cancer [4], the efficacy of this agent has been restricted by the acquired resistance in cancer cells [5]. Investigation on the mechanisms underlying paclitaxel resistance in cancer cells can lead to novel strategies to improve the efficacy of the chemotherapeutic agents. B-cell lymphoma/leukemia (BCL-2) is known as a first proto-oncogene with an anti-apoptotic function which belongs to BCL-2 family of proteins acting as key regulators of apoptosis [9]. Some of these proteins including Bcl-2 and Bcl-XL play the anti-apoptotic role while others such as Bad, Bax, and Bid are pro-apoptotic. Our findings add new insights into the mechanisms of resistance to paclitaxel in breast cancer cells
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