Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance

Abstract

Aim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. Methods: The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. Results: The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (P < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC50 value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (P < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. Conclusion: Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.

Synthesis and Biological Evaluation of Chalconesulfonamides: En Route to Proapoptotic Agents with Antiestrogenic Potency

“…The selected breast cancer cell lines differ primarily in the activity of the steroid hormone receptor signaling pathways. Prolonged incubation with the antiestrogen HT resulted in partial inhibition of ERα activity [ 34 ], limiting further application of such treatment. The compound 7e caused a decrease in ERα expression in MCF7 cells; the selected compound at a concentration of 2.5 μM almost completely blocked ERα expression ( Figure 5 ).…”

“…The MCF7, K-562, and HCT-116 cell lines were obtained from the ATCC collection. MCF7/HT2 cell subline was obtained as described in our recent work [ 34 ]. The multidrug-resistant (MDR) subline K-562/4 was obtained via stepwise selection of K-562 cells for survival under continuous exposure to doxorubicin [ 60 ].…”

“…The results regarding antiproliferative activity are summarized in Table 1. Screening of the antiproliferative properties of the synthesized 2-oxo-2phenylethane sulfonamide 11 and chalconesulfonamides 7a-l was performed with an MTT test on breast cancer cells MCF7, hormone-resistant MCF7/HT2 subline [34], leukemia cell line K-562, resistant subline K-562/4 with Pgp [35,36], and colon cancer cells HCT-116. The results regarding antiproliferative activity are summarized in Table 1.…”

Honokiol inhibits the growth of hormone-resistant breast cancer cells: its promising effect in combination with metformin

“…Hydroxytamoxifen (HT) was obtained from Cayman Chemical (Cayman Chemical, USA). The HT-resistant MCF7 subline (MCF7/HT) was established from the parent MCF7 cells by long-term treatment with 5 μM HT ( 29 ).…”

Combined Application of Honokiol and 2-Deoxyglucose against MCF7 Breast Cancer Cells Under Hypoxia

“…However, tamoxifen also has estrogen agonist activity, which may contribute to treatment failure [3]. The resistance to both drugs develops over time through the dysregulation of the PI3K/AKT/mTOR pathway that cross-talks with ERα-mediated signalling [4,5]. At the moment, there are different approaches to the treatment of breast cancer, and the choice of method depends on the genotype of a particular tumour: therapy with PARP inhibitors in the presence of BRCA1/2 and BRCAness TNBC mutations, anthracyclines, taxanes, and platinum-based therapy and immunotherapy with monoclonal antibodies that block CTLA4, PD1 or PDL1 [6].…”