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. 2025 Aug 28;14(8):5109–5126. doi: 10.21037/tcr-2025-1175

Investigation into the sensitivity of adipocytes mediated by the major vault protein (MVP) to chemotherapy for triple-negative breast cancer

Lianjin Qin 1, Ruofan Fei 1, Wenjuan Wang 2,*,✉, Qingjian He 1,*,✉
PMCID: PMC12432768  PMID: 40950669

Abstract

Background

Chemotherapy is an important therapeutic method for treating triple-negative breast cancer (TNBC), and docetaxel is the most commonly used chemotherapy drug for TNBC. Fat cells may increase the aggressiveness of TNBC and reduce the therapeutic effect of docetaxel. This research aimed to examine the mechanisms underlying the reduced chemosensitivity of TNBC to docetaxel.

Methods

Cell migration and invasion experiments revealed that breast cancer cells cocultured with mature adipocytes had increased invasive and migratory capabilities, and decreased sensitivity to docetaxel chemotherapy. Immunofluorescence and Western blot analyses revealed the significant upregulation of major vault protein (MVP) expression in the cocultured breast cancer cells.

Results

Our findings indicated that docetaxel effectively inhibited the proliferation, migration, and invasion of the MDA-MB231 cells. The optimal therapeutic concentration for the MDA-MB231 cells was 1,000 nM, and the optimal treatment duration was 48 hours.

Conclusions

The level of MVP expression appears to influence the chemosensitivity of breast cancer cells to docetaxel. Notably, our results suggest that cocultured breast cancer cells may modulate MVP expression via the Notch1 signaling pathway. Overall, this study provides evidence that adipocytes could influence the chemosensitivity of TNBC cells to docetaxel via MVP expression.

Keywords: Triple-negative breast cancer (TNBC), adipocytes, docetaxel, major vault protein (MVP), Notch1 signaling pathway

Highlight box.

Key findings

• Fat cells may increase the aggressiveness of triple-negative breast cancer (TNBC) and enhanced the resistance of tumor cells to docetaxel and weakened the therapeutic effect. The level of major vault protein (MVP) expression influences the chemosensitivity of breast cancer cells to docetaxel.

What is known, and what is new?

• Docetaxel is the most commonly used chemotherapy drug for TNBC.

• Cocultured breast cancer cells may modulate MVP protein expression via the NOTCH1 signaling pathway.

What is the implication, and what should change now?

• Our findings provide a new perspective on the mechanism of chemotherapy resistance in TNBC and an experimental basis for the development of more effective TNBC treatment strategies. This study not only provided insights into the complex role of fat cells in breast cancer, but also provided new targets and methods for overcoming chemotherapy resistance.

Introduction

Breast cancer is one of the most common malignancies in women worldwide. According to Global Cancer Statistics 2024, there were approximately 2.3 million new cases of breast cancer and 666,000 deaths in women in 2022, accounting for 6.9% of all cancer deaths (1,2). Breast cancer is a highly heterogeneous disease. Its heterogeneity is reflected not only in the biological characteristics of the tumor but also in its clinical presentation, treatment sensitivity, and prognosis. Based on the molecular subtype of the tumor, breast cancer can be divided into many types, among which triple-negative breast cancer (TNBC) is an important subtype (3). The main feature of TNBC is the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 on the surface of cancer cells (4). This special molecular phenotype makes TNBC insensitive to endocrine therapy and molecular-targeted therapy, and thus difficult to treat. However, due to its highly aggressive nature, TNBC responds relatively well to chemotherapy; thus, chemotherapy is one of its main treatments. Docetaxel, a commonly used chemotherapy drug, can inhibit tubulin depolymerization and block the cell cycle, thus inhibiting the proliferation, migration and invasion of cancer cells; it is widely used to treat TNBC (5,6).

In recent years, an increasing number of studies have shown that the tumor microenvironment plays an important role in the occurrence and development of breast cancer (7-9). As important components of the breast cancer microenvironment, fat cells not only play a key role in obesity-related breast cancer but may also influence the biological behavior of cancer cells through multiple mechanisms. Adipose tissue primarily consists of adipocytes and stromal vascular cells, including vascular endothelial cells, smooth muscle cells, pericytes, immune cells, and fibroblasts. Adipocytes release proteins and micro RNAs via exosomes, which subsequently enter circulation following uptake by vascular endothelial cells. Therefore, adipocytes are capable of secreting a range of factors that facilitate the proliferation, migration, and invasion of cancer cells. These factors can enter the systemic circulation via the vasculature of adipose tissue, thereby enhancing tumor invasiveness and metastatic potential (10,11). In addition, clinical and basic studies have shown that adipocyte-derived factors influence the response to chemotherapy drugs and reduce their therapeutic sensitivity (12-15). This phenomenon suggests that understanding the role of adipocytes in TNBC chemotherapy resistance and their mechanism is highly important in improving the therapeutic effect of TNBC.

The major vault protein (MVP) is the core component of the fornix body, and is a multifunctional protein complex that is mainly involved in intracellular drug efflux, stress response regulation, and signaling (16-18). MVP upregulation is an important mechanism of adipose-cell-mediated tumor resistance (19). Therefore, targeted therapy against the MVP or related signaling pathways may become a new strategy to overcome drug resistance in breast cancer. For example, inhibiting MVP expression or its drug efflux function could increase the accumulation of chemotherapy drugs in tumor cells, thereby improving the efficacy of chemotherapy.

This study focuses on in-depth investigation of the influence of adipocytes on the docetaxel sensitivity of TNBC cells and the underlying mechanism. In particular, it focused on the role of the MVP in this process, as its expression level is closely related to the sensitivity of cancer cells to chemotherapy drugs. In addition, it explored the potential mechanisms by which the Notch1 signaling pathway regulates MVP expression in adipocytes. Through this study, we hope to provide a new perspective on the mechanism of chemotherapy resistance in TNBC and an experimental basis for the development of more effective TNBC treatment strategies. This study not only helped to reveal the complex role of fat cells in breast cancer but also provided new targets and methods for overcoming chemotherapy resistance. We present this article in accordance with the MDAR reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1175/rc).

Methods

Cell line and culture

A human breast cancer cell line (MDA-MB-231) and mouse embryonic fibroblasts (3T3-L1) were purchased from the American Typical Culture Collection (ATCC; Manassas, VA, USA) and validated. All the cells were cultured following instructions from the ATCC.

The human breast cancer cell line (MDA-MB-231) was cultured in complete medium (L15, Pricella, Wuhan, China); the mouse embryonic fibroblasts (3T3-L1) were cultured in fibroblast-specific medium (Pricella); the “adipocytes” were differentiated from fibroblasts for 10 to 14 days (85% of which accumulated lipid droplets); and the cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Gaithersburg, MD, USA). All the strains were cultured at 37 ℃ in a humid environment with 5% carbon dioxide (CO2).

The 3T3-L1 cells were inoculated in six-well plates at a density of approximately 3×103 cells/well and cultured with fibroblast-specific medium. The culture medium was replaced every 2 days. When the cell concentration exceeded 85%, the growth medium was replaced with monocyte differentiation-inducing (MDI) medium containing DMEM + 0.5 mmol/L of IBMX (3-isobutyl-1-methylxanthine) + 1 µmol/L of dexamethasone +10 µg/mL of insulin. The MDI medium was replaced with insulin maintenance medium (DMEM + 10 µg/mL of insulin) for an additional 3 days to promote lipid droplet maturation, and the medium was replaced with DMEM after 3 days of continuous culture. The DMEM was replaced every 2 days, and the accumulation of lipid droplets was monitored by oil-red-O staining during induction.

Coculture system

A Transwell culture system (8.0-µm pore size; Nest, Wuxi, China) was used. The fibroblasts were first inoculated in the lower chamber and differentiated into mature adipocytes after 10 to 14 days. The MDA-MB-231 cells were then inoculated in the upper chamber for coincubation.

Docetaxel interferes with MDA-MB-231 cells

The MDA-MB-231 cells were incubated with docetaxel (AbMole, Wuhan, China) in a humid environment with 5% CO2 at 37 ℃ for 48 hours.

CCK-8 cell proliferation tests

The MDA-MB-231 cells were inoculated in 96-well Petri dishes at a density of 1×104 cells/well. After 2 days of growth, the cells were treated with docetaxel (0, 1, 10, 100, 1,000, or 10,000 nM) for 24, 48, or 72 hours, respectively. A 10-µL mixture from the Cell Counting Kit-8 (CCK-8) (AbMole) was added to each well, after which the 96-well Petri dishes were incubated in a humid environment of 5% CO2 at 37 ℃ for 1 hour. The absorbance was measured at 450 nm using an optical density reader (Bio-Rad, Hercules, CA, USA). All the measurements were taken three times.

Wound healing cell migration test

Cell migration was observed through a wound healing test. Over time, the cells grew, affecting the width of the scratch. Approximately 1×105 MDA-MB-231 cells/mL were added to each well with a marker on the back of the six-well plate and cultured until the percentage of confluent cells was greater than 90%. The cell monolayer was scratched with the tip of a 10-µL pipette, and the cells were washed three times with phosphate buffered saline (PBS). The labelled cells were removed and treated with different drug concentrations. The cells were placed in a 5% CO2 incubator at 37 ℃ for 48 hours. Images were taken using a microscope equipped with a digital camera (Nikon, Tokyo, Japan) and subsequently analyzed using ImageJ software.

Flow cytometry

The MDA-MB-231 cells were inoculated in six-well Petri dishes at a density of 2×105 cells/well. After the above intervention, the cells were washed three times with pre-cooled PBS and collected with 0.25% trypsin solution (Beyotime Biotechnology, Shanghai, China) without ethylenediaminetetraacetic acid (EDTA). The cells were subsequently transferred to an Eppendorf tube and centrifuged at 4 ℃ at 1,500 rpm. First, for the apoptosis assay, 1× buffer was added to the flow tube according to the protocol of the fluorescein isothiocyanate (FITC) Annexin V Apoptosis Detection Kit (BD PharmingenTM, New Jersey, USA), and the number of cells per tube was calculated to be 1×106/mL. Annexin V (5 µL) was added, and the cells were incubated for 15 minutes. Next, 5 µL of propidium iodide (PI) was added, and the cells were incubated in the dark for 5 minutes. Second, the reactive oxygen species (ROS) underwent photoactivation. Specifically, 10 µM of DCFH-DA (2',7'-dichlorodihydrofluorescein diacetate) (Biosharp, Hefei, Anhui, China) was added to the cells, which were then incubated at 37 ℃ for 20 minutes, during which flipping was performed every 3–5 minutes to ensure that the cell count was 1×106/mL. Third, to examine the cell cycle, the cells were resuspended overnight in 75% ethanol at 4 ℃. Next, 500 µL of PI/RNAase staining buffer (BD PharmingenTM, New Jersey, USA) was added, and the cells were incubated in the dark for 15 minutes. The cells were transferred into a flow tube for testing. The test was performed using a Beckman Cyto FLEX instrument (BD PharmingenTM, New Jersey, USA).

Immunofluorescent labelling

The MDA-MB-231 cells were differentiated in 24-well Petri dishes at a density of 5×104 cells per well using the above method. For labelling, the cells were fixed in 4% paraformaldehyde for 15 minutes and washed three times in cold PBS + Tween-20 (PBST). Next, the cells were ruptured at room temperature with 0.1% PBS-Triton X-100 (Solarbio, Beijing, China) for 5 minutes before being washed three times with PBST. The cells were then infiltrated and blocked with 10% PBS-normal goat serum (Solarbio, Beijing, China) and incubated at 37 ℃ for 1.5 hours. The samples were then diluted in a universal antibody mixture (NCM Biotech, Suzhou, China) with the following primary antibodies (1:200) and incubated overnight at 4 ℃: anti-MVP (Abcam, Shanghai, China) and anti-CD31 (Proteintech, Wuhan, China). According to the fluorescence requirements, the experiment was carried out under dark- and light-resistant conditions. The cells were washed three times with 1× PBST and then incubated at room temperature for 1 hour with secondary antibodies diluted with the following universal antibody diluents (1:500): CoraLite 488 conjugate (Proteintech, Wuhan, China) and CoraLite 594 conjugate (Proteintech, Wuhan, China). The cells were then stained with DAPI (4',6-diamidino-2-phenylindole) (AbMole, Shanghai, China) and diluted to 10 µg/mL for 5 minutes at room temperature. Finally, the cap layer was observed using inverted fluorescence microscopy (Nikon, Japan) and two-photon laser confocal microscopy (Zeiss, Germany). ImageJ software was then used to calculate the positive signal area, and Prism software was used for the data analysis and histogram display.

Western blotting

The protein was extracted with radioimmunoprecipitation buffer and benzoyl fluoride (phenylmethylsulphonyl fluoride) (Shanghai, China) at a ratio of 100:1. The protein concentration was determined using a bicinchoninic acid assay kit (Biosharp) using sample loading buffer with a volume ratio of 5:1 (Biosharp).

After denaturation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the proteins were transferred to polyvinylidene fluoride (PVDF) membranes and treated with 5% skim milk powder (Sigma, Shanghai, China). CD31, MVP, α-Tubulin, caspase-3, NOTCH1, DLL4, JAG1, β-actin, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; Proteintech, Wuhan, China) were incubated at –20 ℃ overnight. The PVDF membranes were washed with TBST and then with secondary antibody. Finally, the membranes were washed again and incubated in electrochemiluminescence substrate (Fisher, Wuhan, China). The images were analyzed by ImageJ software, and the results were uniformly naturalized.

Transwell experiment

A Transwell assay (8.0-µm aperture, Nest, Wuxi, China) was used to detect the migration and invasion ability of the cells. The upper chamber of the cell mixture was coated with 50 µL of Matrigel (Corning Glass Works, Corning, Suzhou, China) for the invasion analysis. Experimental cells (5×104 cells/mL) treated with different concentrations were inoculated into the upper chamber, which contained 200 µL of serum-free DMEM, and the lower chamber was coated with 500 µL of DMEM, containing 10% fetal bovine serum. The cells were cultured at 37 ℃ and 5% CO2 for 12 hours (migration) or 24 hours (invasion), and stained with 0.1% crystal violet. The stained cells were counted under a light microscope (CKX41; Olympus Corporation, Tokyo, Japan), and five fields of view were randomly selected for each sample.

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis

Total RNA was extracted using TRIzol (Takara, Tokyo, Japan). To quantify messenger RNA (mRNA), complementary DNA was prepared using the PrimeScriptTM RT Reagent Kit (Takara). Real-time PCR was performed on a Bio-Rad CFX-96 Real-Time System (Bio-Rad) with SYBR Green (Bio-Rad) as the fluorescent dye. The relative RNA expression levels were determined using the relative standard curve method (2−ΔΔCt). PCR primer synthesis was assisted by biotechnology companies (Sangon Biotech, Shanghai, China). The following primers were used in this study: NOTCH1 (forward: 5'-TGA ATG GCG GGA AGT GTG AA-3'; reverse: 5'-TTG GTG AGG CAG GCA TTG TC-3'); JAG1 (forward: 5'-AAT GGC TAC CGG TGT GTC TG-3'; reverse: 5'-CCC ATG GTG ATG CAA GGT CT-3'); DLL4 (forward: 5'-GCA CTC CCT GGC AAT GTA CT-3'; reverse: 5'-GAC AGG TGC AGG TGT AGC TT-3'); and GAPDH (forward: 5'-GGA AGG AAA TGA ATG GGC AGC-3'; reverse: 5'-TAG GAA AAG CAT CAC CCG GAG-3').

Statistical analysis

All of the experiments were performed at least three times. The statistical analysis was conducted using GraphPad Prism 10.0 software (San Diego, California). Both P<0.05 and P<0.01 were considered statistically significant. A two-way analysis of variance and Tukey’s test were used for multiple comparisons of the data.

Results

Docetaxel inhibits the proliferation and migration of MDA-MB-231

To evaluate the effect of docetaxel on cell proliferation, a CCK-8 assay was used. The MDA-MB-231 cells were treated with 0, 1, 10, 100, 1,000, or 10,000 nM of docetaxel, and different intervention times (24, 48, or 72 hours) were used. The cell proliferation rate decreased as the concentration increased. Compared with that of the other groups, the cell proliferation rate was lowest in the 1,000-nM group after 48 hours of intervention (Figure 1A).

Figure 1.

Figure 1

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The effects of different concentrations (0, 1, 10, 100, 1,000, and 10,000 nM) of docetaxel on the proliferation and migration of MDA-MB-231 cells. (A) The change in cell viability was determined by CCK-8 assay after different concentrations of docetaxel intervention. (B,C) The migration ability of the MDA-MB-231 cells and the percentage of the scratch area (%) were detected by wound healing assay (magnification factor is 20×). Data represent the results of three independent measurements, and are presented as the mean ± standard deviation. ns, P>0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001, compared with the control group. Statistical significance was determined by intragroup comparisons (48 h): ##, P<0.01; ###, P<0.001; ####, P<0.0001, vs. 24 h.

To examine the effect of docetaxel on the migration ability of the MDA-MB-231 cells, different concentrations (1, 10, 100, 1,000, or 10,000 nM) were used for 48 hours. The average migration area of the 1-nM group was 19.82%±1.094%, that of the 10-nM group was 21.38%±0.5872%, that of the 100-nM group was 34.73%±0.4291%, that of the 1,000-nM group was 59.06%±0.5466%, and that of the 10,000-nM group was 47.29%±0.8152%. As the concentration increased, the area of the wound increased, and the cell migration ability decreased, with the maximum average migration area peaking at 1,000 nM (Figure 1B,1C).

Docetaxel arrests MDA-MB-231 cells specifically in the S + G2 phase of the cell cycle

The effect of docetaxel on the proliferation ability of the MDA-MB-231 cells was verified by detecting the cell cycle through flow cytometry (Figure 2A,2B). The S + G2 of the control group was 62.26%±3.189%, that of the 1-nM group was 77.05%±4.092%, that of the 10-nM group was 50.67%±2.436%, that of the 100-nM group was 43.9%±2.007%, that of the 1,000-nM group was 36.43%±2.161%, and that of the 10,000-nM group was 42.17%±3.115%. Compared with those in the control group, the number of cells in the S + G2 phase of cell division in the 1,000-nM group decreased, and the number of cells in the G1 phase of cell division increased. The proportion of S + G2 in the 1,000-nM group was significantly reduced (Figure 2C).

Figure 2.

Figure 2

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Flow cytometry was used to detect the effects of different drug concentrations on the cell cycle. (A) The effects of different drug concentrations on the cell cycle. (B,C) The proportion of the G + S period among the different groups was described and statistically analyzed. The data represent the results of three independent measurements, and are presented as the mean ± standard deviation. ns, P>0.05; *, P<0.05; **, P<0.01; ***, P<0.001, compared with the control group. CV, coefficient of variation; PE, phycoerythrin; RMSD, root mean square deviation.

Docetaxel induces apoptosis in MDA-MB-231 cells

Cell apoptosis was assessed using flow cytometry. The apoptosis rates for the control and treatment groups were as follows: control group (9.433%±0.2186%), 1-nM group (15.23%±0.4167%), 10-nM group (16.74%±0.3024%), 100-nM group (19.13%±0.5179%), 1,000nM group (24.41%±0.4656%), and 10,000-nM group (18.08%±0.6269%). Compared with that in the control group, cell apoptosis was significantly elevated in all treatment groups, with the most pronounced increase observed at the 1,000 nM concentration (Figure 3A,3B). The Western blot analysis revealed that the caspase-3 protein expression levels were lower in all treatment groups than the control group, with a particularly significant decrease noted in the 1,000-nM group (Figure 3C,3D).

Figure 3.

Figure 3

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Detection of apoptosis in MDA-MB-231 cells at various concentrations. (A,B) Flow cytometry analysis was employed to assess cell apoptosis. (C,D) Western blotting was used to evaluate the expression levels of the apoptosis-related proteins. Specifically, (C) shows the expression level of Caspase-3. The data are presented as the mean ± standard error from three independent experiments. Statistical significance compared with the control group is indicated as follows: ns, P>0.05; *, P<0.05; ***, P<0.001; ****, P<0.0001. FITC, fluorescein Isothiocyanate; PE, phycoerythrin.

Docetaxel affects the vascular invasion capability of MDA-MB-231 cells

To investigate the effects of docetaxel on vascular invasion in the MDA-MB-231 cells, we conducted immunofluorescence staining using CD31 as a marker. The results revealed that varying concentrations of docetaxel had significantly different effects on these cells. Specifically, the areas of the CD31-positive signal were 45.68±1.783 in the control group, 34.25±1.894 in the 10-nM group, 29.50±1.753 in the 100-nM group, 18.13±1.749 in the 1,000-nM group, and 33.72±1.325 in the 10,000-nM group. Notably, the smallest positive signal area was observed at a concentration of 1,000 nM, suggesting that this concentration had the strongest inhibitory effect on MDA-MB-231 cell invasion (Figure 4A,4B). Additionally, the Western blot analysis revealed a decreasing trend in CD31 protein expression across all groups following docetaxel treatment. Consistent with the immunofluorescence findings, the 1,000-nM concentration resulted in the lowest CD31 protein expression, further confirming its potent inhibitory effect on cellular invasion (Figure 4C,4D).

Figure 4.

Figure 4

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Effects of different concentrations of docetaxel on the vascular invasion ability of MDA-MB231 cells. (A,B) Immunofluorescence detection of CD31. (C,D) Western blotting was used to detect the protein expression of CD31. (C) Expression level of CD31. The data represent three independent measurements, and are presented as the mean ± standard error. *, P<0.05; **, P<0.01; ***, P<0.001, compared with the control group. DAPI, 4',6-diamidino-2-phenylindole​.

MVP expression is associated with the drug sensitivity of MDA-MB-231 cells

To investigate the correlation between the MVP expression levels and drug sensitivity in the MDA-MB-231 cells, we conducted immunofluorescence assays to quantify MVP expression. The results revealed significant differences in MVP expression among the cells treated with various drug concentrations. Specifically, the areas of the MVP-positive signals were as follows: control group (41.40±1.819), 10-nM group (28.13±2.021), 100-nM group (16.22±1.669), 1,000-nM group (7.911±1.689), and 10,000-nM group (21.24±1.792). Notably, among the groups the, MVP-positive signal area was the lowest at a concentration of 1,000 nM (Figure 5A,5B). Additionally, the Western blot analysis revealed that MVP expression was lower in the 1,000-nM group than the other groups (Figure 5C,5D). Collectively, these findings suggest that the drug sensitivity of the MDA-MB-231 cells was associated with the MVP expression levels.

Figure 5.

Figure 5

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The effect of varying concentrations of docetaxel on the MVP expression levels in MDA-MB-231 cells. (A,B) The immunofluorescence staining results for the MVP. (C,D) Western blot analyses of MVP expression. The data are representative of three independent experiments and are expressed as the mean ± standard error. Statistical significance compared with the control group is indicated as follows: ns, P>0.05; *, P<0.05; **, P<0.01; ***, P<0.001. DAPI, 4',6-diamidino-2-phenylindole​; MVP, major vault protein.

Adipocytes facilitate the migration and invasion of MDA-MB-231 cells

To further investigate the effect of adipocytes on the migration and invasion capabilities of the MDA-MB-231 cells, we employed a Transwell assay to evaluate these properties in both the MDA-MB-231 cells and cocultured cells. Our results revealed that the migration and invasion abilities of the cocultured cells were significantly greater than those of the MDA-MB-231 cells alone (Figure 6A-6F).

Figure 6.

Figure 6

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Migration and invasion of MDA-MB-231 cells and cocultured cells. (A,B) Scratch experiments for each group (magnification factor is 20×). (C,D) Migration experiments for each group. (E,F) Intrusion experiments for each group. (C,F) were stained using crystal violet staining method. The expression levels of α-Tubulin in groups (G,H) were detected by Western blot. Data are presented as the mean ± standard errors from three independent experiments. Statistical significance was determined by intergroup comparisons: *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001; #, P<0.05; ##, P<0.01; ###, P<0.001; ####, P<0.0001, vs. 0-nM group.

Specifically, in the 0nM-group, the average migration area of the MDA-MB-231 cells was 27.74±0.6787, while for the cocultured cells, it was 21.71±0.7084; in the 100-nM group, the average migration area of the MDA-MB-231 cells was 37.63±0.5987, while for the cocultured cells, it was 28.01±0.1849; and in the 1,000-nM group, the average migration area of the MDA-MB-231 cells was 47.77±0.3677, while for the cocultured cells, it was 38.52±0.4188.

In the 0-nM group, the number of migrated MDA-MB-231 cells was 471.333±7.796, while for the cocultured cells, it was 573.667±11.667; in the 100-nM group, the number of migrated MDA-MB-231 cells was 156.000±8.622, while for the cocultured cells, it was 284.000±11.930; and in the 1,000-nM group, the number of migrated MDA-MB-231 cells was 83.667±3.480, while for the cocultured cells, it was 133.667±4.910.

In terms of invasion, in the 0-nM group, the number of invaded MDA-MB-231 cells was 59.00±1.155, while for the cocultured cells, it was 68.333±1.764; in the 100-nM group, the number of invaded MDA-MB-231 cells was 46.333±1.453, while for the cocultured cells, it was 54.333±1.453; and in the 1,000-nM group, the number of invaded MDA-MB-231 cells 28.333±1.453, while for the cocultured cells, it was and 41.667±1.202.

Additionally, the Western blot analysis revealed a significant increase in α-Tubulin protein expression in the cocultured cells compared with that in the MDA-MB-231 cells (Figure 6G,6H).

MDA-MB-231 cells cocultured with adipocytes had significantly increased MVP expression levels

Immunofluorescence detection was performed to examine the difference in the MVP expression levels between the cocultured cells and MDA-MB-231 cells. The results revealed that the MVP expression levels of the two groups differed significantly. In the 0-nM group, the area of the MVP-positive signal in the MDA-MB-231 cells was 46.907±0.189, and that of the cocultured cells was 54.485±1.065. In the 100-nM group, the area of the MVP-positive signal in the MDA-MB-231 cells was 39.037±0.684, and that of the cocultured cells was 46.662±1.091. In the 1,000-nM group, the area of the MVP-positive signal in the MDA-MB-231 cells was 31.636±0.691, and that of the cocultured cells was 43.363±1.097. Comparing the groups, the area of the MVP-positive signal in the two groups of cells was the smallest when the concentration was 1,000 nM, and the MVP expression level in the co-culture group was greater the MDA-MB-231 group (Figure 7A,7B).

Figure 7.

Figure 7

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Expression levels of MVP in MDA-MB-231 cells and cocultured cells. (A,B) Immunofluorescence staining for MVP. (C,D) A Western blot analysis was conducted to assess MVP expression. The data are presented as the mean ± standard error from three independent experiments. Statistical significance between groups is indicated as follows: * P<0.05, ** P<0.01, *** P<0.001. ****, P<0.0001. Statistical significance was determined by intragroup comparisons: #, P<0.05; ##, P<0.01; ###, P<0.001; ####, P<0.0001, vs. 0-nM group. MVP, major vault protein.

Western blotting was used to detect MVP expression in the cocultured cells and MDA-MB-231 cells. After intervention with the same drug concentration in the two groups of cells, MVP expression was the lowest in the 1,000-nM group, and the MVP expression level was significantly greater in the cocultured cells than the MDA-MB-231 cells (Figure 7C,7D).

Cocultured cells affect MVP expression via the Notch1 signaling pathway

To explore the mechanism affecting the MVP expression level in the cocultured cells, Western blotting was used to detect the expression levels of NOTCH1/DLL4/JAG1. The results revealed that the expression levels of NOTCH1/DLL4/JAG1 decreased when the concentration was 1,000 nM. As mentioned above, the MVP expression level decreased significantly at a concentration of 1,000 nM. The findings suggest that the cocultured cells also affect MVP expression via the Notch1 signaling pathway (Figure 8).

Figure 8.

Figure 8

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Protein and relative messenger RNA levels of the Notch1 signaling pathway in coculture cells. (A-D) The protein expression levels of NOTCH1, DLL4 and JAG1. (E-G) The relative mRNA levels of NOTCH1, DLL4 and JAG1. Data are presented as the mean ± standard error from three independent experiments. Statistical significance was determined relative to the control group: ns, P>0.05; *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001.

Discussion

The effect of docetaxel on MDA-MB-231 cells

Inhibitory effects on proliferation

The experimental results showed that docetaxel significantly inhibited the proliferation of the MDA-MB-231 cells. The CCK-8 assay results revealed a dose-dependent decrease in cell proliferation as the docetaxel concentration increased. Notably, at a concentration of 1,000 nM, the proliferation rate was minimal after 48 hours of drug exposure (Figure 1A). A study has validated the efficacy and dose-response relationship of docetaxel in TNBC (20). The observed dose-dependent inhibitory effect underscores the potential clinical utility of docetaxel, and provides a critical foundation for investigating its specific mechanisms of action and optimizing treatment protocols. Additionally, this evidence highlights the importance of precise dose control in chemotherapy to enhance therapeutic outcomes while minimizing adverse effects.

This study revealed that the survival rate of cells at 10,000 nm was greater than that at 1,000 nM, which might be due to the following reasons: (I) Above a certain threshold of drug concentration, docetaxel may trigger an overstress response in cells, activate protective pathways, and even induce non-specific toxicity (such as lysosomal rupture), ultimately leading to rapid cell death or irreversible necrosis, which in turn reduces experimentally observable cell survival; (II) High concentrations of docetaxel may induce compensatory activation of the Notch1 signaling pathway, which may promote the recovery of MVP expression and ultimately lead to increased cell survival. Further mechanistic studies need to be conducted to clarify this response.

Inhibitory effects on migration

The wound healing assay revealed that docetaxel significantly affected the migratory capacity of the MDA-MB-231 cells. The area changes observed in the scratch assay following treatment with varying concentrations of docetaxel indicated a dose-dependent increase in cell migration (Figure 1B,1C). This phenomenon may be attributed to the cytotoxic effects of docetaxel at higher concentrations (21). Notably, the significantly reduced migratory ability at 1,000 nM suggests that high concentrations of docetaxel might influence cellular behavior through alternative mechanisms, such as cytoskeletal rearrangement or the activation of specific migration-related signaling pathways. These findings provide novel insights for future investigations into the complex biological effects of docetaxel at elevated concentrations.

Cell-cycle arrest effects

The flow cytometry analysis demonstrated that docetaxel induced S-phase arrest in the MDA-MB-231 cells. At a concentration of 1,000 nM, there was a significant decrease in the proportion of cells in the S phase, accompanied by an increase in the proportion of cells in the G1 phase (Figure 2A,2B). This observation aligns with the established mechanism whereby docetaxel inhibits microtubule depolymerization, thereby blocking cell-cycle progression and preventing the transition from the S phase to the G2/M phase. Consequently, docetaxel effectively interferes with mitosis, inhibiting cell division and proliferation. The cell-cycle arrest effect is a critical mechanism underlying the anti-tumor activity of docetaxel, underscoring its pivotal role in suppressing tumor cell proliferation. Moreover, these findings support the clinical application of docetaxel in breast cancer treatment and provide a theoretical foundation for optimizing its therapeutic efficacy across different cancer types.

Promotion of apoptosis

The flow cytometry analysis revealed a significant increase in the apoptosis rate of the MDA-MB-231 cells following docetaxel treatment, particularly at a concentration of 1,000 nM (Figure 3A,3B). The Western blotting results corroborated this observation, revealing a significant decrease in the expression level of the apoptosis-related protein caspase-3 in the 1,000-nM group (Figure 3C,3D). These findings indicate that docetaxel exerts its anti-tumor effects through two mechanisms: the inhibition of cell proliferation, and the promotion of apoptosis. As docetaxel is a key executor of apoptosis, the reduced expression of caspase-3 suggests that docetaxel may induce programmed cell death by activating apoptotic signaling pathways, such as the mitochondrial and death receptor pathways (22,23). This dual mechanism enhances the efficacy of docetaxel in treating TNBC and provides valuable insights into its potential therapeutic mechanisms for other types of tumors.

Inhibition of vascular invasion

The immunofluorescence detection and Western blotting results showed that docetaxel significantly inhibited the vascular invasion of the MDA-MB-231 cells. As the drug concentration increased, both the area of the CD31-positive signal and the protein expression levels decreased significantly, with the most pronounced inhibitory effect observed at a concentration of 1,000 nM (Figure 4). These findings suggest that docetaxel not only effectively suppresses cell proliferation and promotes apoptosis but also reduces tumor angiogenesis by downregulating the expression of angiogenesis-related markers, thereby inhibiting tumor invasion and metastasis. A reduction in vascular invasion ability is particularly critical for controlling the progression of TNBC, as this type of tumor typically has high invasiveness and metastatic potential. This mechanism of action of docetaxel offers novel insights into the development of comprehensive treatment strategies for TNBC, especially when docetaxel is combined with antiangiogenic agents to more comprehensively inhibit tumor growth and dissemination.

The effect of adipocytes on MDA-MB-231 cells

The Transwell assay revealed that compared with the MDA-MB-231 cells cultured alone, the cocultured cells exhibited significantly enhanced migration and invasion capabilities (Figure 6A-6D). Our findings suggest that adipocytes potentiate the invasiveness and metastatic potential of TNBC cells via specific mechanisms, potentially diminishing the efficacy of chemotherapeutic agents. Adipocytes may facilitate cancer cell migration and invasion by secreting cytokines and growth factors such as IL-6, HGF, and IGF-1, which activate signaling pathways such as the PI3K/Akt and MAPK pathways in cancer cells, thereby enhancing their invasive properties. Moreover, adipocytes can further promote tumor growth and metastasis by modulating the metabolic state of the tumor microenvironment and providing essential nutrients and support (24-26). These observations indicate that in breast cancer treatment, alongside traditional chemotherapy drugs, targeting adipocytes in the tumor microenvironment should be considered to more comprehensively inhibit tumor invasion and metastasis and improve therapeutic outcomes.

The immunofluorescence and Western blot analyses showed that compared with the MDA-MB-231 cells cultured alone, the cocultured cells showed a significant increase in MVP expression (Figure 7). Notably, at a docetaxel concentration of 1,000 nM, MVP expression was significantly greater in cocultured cells than the cells cultured alone. These findings suggest that adipocytes may increase docetaxel resistance in MDA-MB-231 cells by increasing MVP expression, thereby reducing the effectiveness of chemotherapy.

This mechanism elucidates the critical role of adipocytes in tumor drug resistance, and offers a novel perspective for understanding the relationship between the tumor microenvironment and chemotherapy resistance. Specifically, the MVP, through its drug efflux pump function, can expel chemotherapeutic drugs (e.g., docetaxel) from cells, thereby reducing intracellular drug accumulation, mitigating their cytotoxic effects, and ultimately contributing to the development of drug resistance. Moreover, adipocytes secrete various factors associated with the tumor microenvironment (e.g., leptin, adiponectin, and IL-6) (27,28). These factors directly or indirectly influence tumor cells, leading to the increased expression of the MVP. By activating specific signaling pathways (e.g., the NF-κB, STAT3, and ERK pathways), these factors increase the transcription and translation of the MVP, thereby increasing the drug efflux ability of tumor cells (29-31). Further, adipocytes serve not only as primary sites for energy storage but also as key regulators in the tumor microenvironment. Through interactions with tumor cells, adipocytes alter the composition and function of the tumor microenvironment, further enhancing tumor cell drug resistance. For example, adipocytes can secrete matrix metalloproteinases, degrade the extracellular matrix, and promote tumor invasion and metastasis; simultaneously, they can regulate tumor angiogenesis and inflammatory responses, providing more favorable survival conditions for tumor cells (32,33).

Correlation between MVP expression and drug sensitivity

The experimental results demonstrated that docetaxel intervention led to a dose-dependent decrease in the protein expression level of MVP in the MDA-MB-231 cells. Both the CCK-8 assays and immunofluorescence analyses revealed that at a concentration of 1,000 nM and after 48 hours of docetaxel treatment, the MVP expression level reached its nadir (Figure 5). This finding was consistent with the observed reduction in the cell proliferation rate, further corroborating the critical role of the MVP in docetaxel efficacy. The MVP is a multifunctional protein involved in various cellular processes, including cell-cycle regulation, apoptosis, and chemoresistance (34). The downregulation of MVP expression may indicate the inhibitory effect of docetaxel on cell-cycle progression and the survival signaling pathways. Consequently, the MVP could serve as a potential biomarker for evaluating the therapeutic response and prognosis of patients receiving docetaxel treatment. Moreover, combination therapies targeting the MVP may enhance docetaxel efficacy, mitigate drug resistance, and offer a more effective treatment strategy for TNBC patients.

This study further revealed that the MVP is not only associated with cell proliferation and apoptosis but may also serve as a critical marker of multidrug resistance. Its expression level is closely correlated with the sensitivity of cancer cells to chemotherapeutic agents (35,36). Through immunofluorescence and Western blot analyses, we observed a significant reduction in MVP expression following docetaxel intervention, particularly at a concentration of 1,000 nM. This decrease was consistent with the increased sensitivity of the cells to the drug. These findings may offer a novel perspective for addressing chemotherapy resistance in TNBC. By downregulating MVP expression, docetaxel may facilitate increased intracellular accumulation of the drug, thereby increasing its anti-tumor efficacy. Moreover, therapeutic strategies targeting the MVP could overcome chemotherapy resistance and improve treatment response rates. Future research should investigate the potential synergistic effects of combining MVP-targeted therapies with other drugs to develop more effective treatment regimens and improve both the survival rate and quality of life of TNBC patients.

Adipocytes modulate MVP expression via the Notch1 signaling pathway

Adipocytes modulate MVP expression via the Notch1 signaling pathway, thereby enhancing chemoresistance in MDA-MB-231 breast cancer cells and significantly diminishing the efficacy of docetaxel chemotherapy. This discovery not only extends our understanding of cell interactions in the tumor microenvironment, but also identifies potential therapeutic targets for the development of novel treatment strategies. The Notch signaling pathway is a highly conserved mechanism of intercellular communication that plays a critical role in development and various physiological processes. On binding to ligands such as DLL1, DLL4, Jagged1, and Jagged2, Notch receptors (Notch1–4) undergo cleavage, releasing the notch intracellular domain (NICD), which translocates to the nucleus to activate downstream target gene expression (37-39). In oncology, the aberrant activation of the Notch signaling pathway is closely associated with tumorigenesis, progression, and chemoresistance in various malignancies (40).

Research indicates that adipocytes secrete Notch1 ligands (e.g., Jagged1 and DLL4) bind to the Notch1 receptor on MDA-MB-231 cells, activating the Notch1 signaling pathway (41-44). Specifically, adipocyte-secreted Notch1 ligands such as Jagged1 and DLL1 specifically bind to the Notch1 receptor on MDA-MB-231 cells, leading to receptor activation. The activated Notch1 receptor is subsequently cleaved by γ-secretase, releasing NICD, which translocates into the nucleus and binds to the transcription factor CSL [CBF1/Su(H)/Lag-1], forming a complex that activates the transcription of downstream target genes, including the MVP. These findings suggest that adipocytes regulate MVP expression through the Notch1 signaling pathway, thereby enhancing chemoresistance in MDA-MB-231 cells.

The current experimental findings showed that following the intervention of cocultured cells with 1,000 nM docetaxel, the protein expression levels of NOTCH1, DLL4, and JAG1 were significantly reduced (Figure 8). These findings indicate that the Notch1 signaling pathway may play a crucial role in adipocytes, influencing MVP expression. Further experiments revealed that the activation of the Notch1 signaling pathway is closely associated with the MVP expression levels. On docetaxel intervention in cocultured cells, the inhibition of the Notch1 signaling pathway resulted in a significant decrease in MVP expression. These results suggest that adipocytes may increase MVP expression by activating the Notch1 signaling pathway, thereby increasing the chemoresistance of MDA-MB-231 cells. These findings provide novel insights into the role of adipocytes in chemotherapy resistance in TNBC.

Conclusions

In summary, this study systematically elucidated the inhibitory effects of docetaxel at various concentrations on the proliferation, migration, invasion, and cell-cycle progression of the MDA-MB-231 cells through a series of experiments. These findings suggest that the MVP plays a crucial role in docetaxel efficacy, and that its reduced expression may increase cancer cell sensitivity to docetaxel by inhibiting proliferation and invasion. Further, this study revealed that adipocytes significantly enhance the migratory and invasive abilities of MDA-MB-231 cells while simultaneously increasing MVP expression. This study revealed that the Notch1 signaling pathway may regulate MVP expression in the tumor microenvironment, thereby influencing the chemosensitivity of cancer cells. Future research should explore the specific molecular mechanisms by which the Notch1 signaling pathway mediates increased MVP expression in adipocytes, including the involvement of specific ligand-receptor interactions, the activation of downstream signaling cascades, and their effects on MVP transcription and translation.

Limitations

This study revealed the potential mechanism by which adipocytes regulate the sensitivity of MDA-MB231 cells to docetaxel through the MVP, but it had certain limitations. First, this study simulated the tumor microenvironment through a Transwell coculture system, which cannot fully replace the complex tumor microenvironment in vivo. Second, the adipocytes in this study were induced and differentiated mainly by murine 3T3-L1 fibroblasts, while MDA-MB231 cells are human cell lines, and the source of adipocytes might affect the regulatory mode of MVP expression. Third, this study revealed a correlation between the Notch1 signaling pathway and the downregulation of MVP expression but did not directly prove a causal relationship between the two, which should be verified by gene knockout or inhibitor interventions. Finally, the correlation between MVP expression in patients’ tumors and prognosis needs to be further confirmed with clinical samples.

Supplementary

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Acknowledgments

None.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1175/rc

Funding: This work was supported by the Huzhou Science and Technology Bureau of Zhejiang Province Project (No. 2021GYB04).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1175/coif). The authors have no conflicts of interest to declare.

(English Language Editor: L. Huleatt)

Data Sharing Statement

Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1175/dss

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    Supplementary Materials

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    DOI: 10.21037/tcr-2025-1175

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