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Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review)

  • Authors:
    • Wenya Xu
    • Shiyao Kang
    • Shaochen Xin
    • Yanbin Wu
    • Yuan Zhao
    • Miaomiao Sheng
  • View Affiliations / Copyright

    Affiliations: Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China, Department of Thyroid and Breast Surgery, Kunming University of Science and Technology Affiliated Puer City People's Hospital, Puer, Yunnan 665000, P.R. China
    Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 162
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    Published online on: July 22, 2026
       https://doi.org/10.3892/or.2026.9167
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Abstract

Breast cancer has the highest incidence among malignant tumors in women worldwide. Although targeted therapy, chemotherapy, and endocrine therapy have achieved significant efficacy, acquired resistance remains a major challenge affecting patient prognosis. The present review systematically outlines five core mechanisms of resistance to breast cancer treatment, including overexpression of ATP‑binding cassette transporters that reduce intracellular drug accumulation; a hypoxic and immunosuppressive tumor microenvironment, together with breast cancer stem cells, that sustains stemness and impairs treatment response; DNA methylation, histone modifications, and non‑coding RNAs that mediate epigenetic reprogramming, leading to silencing of tumor suppressors or activation of resistance pathways; compensatory activation of multiple DNA damage repair pathways, including homologous recombination, non‑homologous end joining, base excision repair, nucleotide excision repair, and mismatch repair, which compromises the efficacy of chemotherapy and poly (ADP‑ribose) polymerase inhibitors; and metabolic reprogramming involving glycolysis, amino acid, nucleotide, and lipid metabolism that supplies tumor cells with energy, reducing equivalents, and biomass for proliferation, while simultaneously promoting immune evasion. Corresponding to these mechanisms, this review also summarizes potential therapeutic strategies, including combined targeted therapy, immunotherapy, and novel drug delivery systems. Therefore, a comprehensive dissection of the multidimensional networks mediating therapy resistance in breast cancer will provide both theoretical foundations and practical pathways for discovering novel biomarkers, optimizing precision combination therapies, and ultimately prolonging patient survival.
View Figures

Figure 1

ABC transporter-mediated multidrug
resistance in breast cancer. ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2
(BCRP) actively efflux chemotherapeutic drugs, such as paclitaxel,
with ABCC1 function assisted by GSH. Hypoxia/HIF-α and growth
factor-activated PI3K/AKT/mTOR, MAPK/ERK, and NF-κB pathways
upregulate these transporters. Nanocarrier systems co-delivering
ABC inhibitors and drugs bypass efflux to enhance intracellular
retention and therapeutic efficacy. ABC, ATP binding cassette;
ABCB1, ABC subfamily B member 1; P-gp P-glycoprotein; ABCC1, ABC
subfamily C member 1; MRP1, multidrug resistance protein 1; ABCG2,
ABC subfamily G member 2; BCRP, breast cancer resistance protein;
GSH, glutathione; HIF-1α, hypoxia-inducible factor; PI3K,
phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR,
mammalian target of rapamycin; MAPK, mitogen-activated protein
kinase; ERK, extracellular signal-regulated kinase; NF-κB, nuclear
factor-κB; p-, phosphorylated.

Figure 2

Schematic of tumor
microenvironment-mediated drug resistance in breast cancer. (A)
Hypoxia-induced HIF-1α/VEGF signaling promotes abnormal
angiogenesis and drug barrier formation. (B) Immunosuppressive
cells (TAMs, MDSCs, Tregs and CAFs), metabolic competition,
PD-1/PD-L1 axis and ECM barrier suppress antitumor immunity. (C)
PI3K/AKT/mTOR and Wnt/β-catenin pathways drive BCSC stemness and
EMT, conferring therapeutic resistance. HIF-1α, hypoxia-inducible
factor; VEGF, vascular endothelial growth factor; TAMs,
tumor-associated macrophages; MDSCs, myeloid-derived suppressor
cells; Tregs, regulatory T cells; CAFs, cancer-associated
fibroblasts; PD-1, programmed cell death protein 1; PD-L1,
programmed death ligand 1; ECM, extracellular matrix; PI3K,
phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR,
mammalian target of rapamycin; BCSC, breast cancer stem cell; EMT,
epithelial-mesenchymal transition; MAPK, mitogen-activated protein
kinase; ERK, extracellular signal-regulated kinase; CAR-T, chimeric
antigen receptor T cell; ICIs, Immune checkpoint inhibitors;
CDK4/6, cyclin-dependent kinases 4 and 6.

Figure 3

Epigenetic regulation of MDR in
breast cancer. (A) DNA methylation by DNMTs silences tumor
suppressors, such as BRCA1, and activates resistance genes, such as
ABCB1, reversed by DNMTi/PRMTi. (B) Histone modifications
(acetylation, phosphorylation, ubiquitination) regulate oncogene
expression and Wnt/β-catenin-mediated DNA repair and metastasis.
(C) Non-coding RNAs (lncRNAs, circRNAs, miRNAs) modulate ABC
transporter expression, EMT and mRNA stability. MDR, multidrug
resistance; DNMTs, DNA methyltransferases; BRCA1, breast cancer
susceptibility gene 1; ABCB1, ABC subfamily B member 1; DNMTi, DNA
methyltransferase inhibitors; PRMTi, protein arginine
methyltransferase inhibitors; lncRNAs, long non-coding RNAs;
miRNAs, microRNAs; circRNAs, circular RNAs; ABC, ATP binding
cassette; EMT, epithelial-mesenchymal transition; HATi, histone
acetyltransferase inhibitors; HAT, histone acetyltransferase; HDAC,
histone deacetylase; HDACi, histone deacetylase inhibitors.

Figure 4

DNA damage repair pathways in breast
cancer. The schematic depicts BER, HRR, NHEJ, NER, and MMR
mechanisms. PARPi selectively induce cell death via synthetic
lethality in BRCA1/2-deficient tumors. Compensatory upregulation of
these pathways mediates resistance to chemotherapy and PARPi. BER,
base excision repair; HRR, homologous recombination repair; NHEJ,
non-homologous end joining; NER, nucleotide excision repair; MMR,
mismatch repair; PARP, poly(ADP-ribose) polymerase inhibitors;
BRCA1/2, breast cancer susceptibility genes 1/2; APE1,
apurinic/apyrimidinic endonuclease 1; CtIP, CtBP-interacting
protein; RPA, replication protein A; MRN, MRE11-RAD50-NBS1 complex;
HR, homologous recombination; FEN1, flap endonuclease 1; POLβ, DNA
polymerase β; LigaseIII, DNA ligase III; XRCC1, X-ray repair
cross-complementing 1; PALB2, partner and localizer of BRCA2;
BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer
susceptibility gene 2; RAD51, RAD51 recombinase; DNA-PKcs,
DNA-dependent protein kinase catalytic subunit; Ligase-IV, DNA
ligase IV; XRCC4, X-ray repair cross-complementing protein 4-like
factor; TFIIH, transcription factorIIH; XPA, xeroderma pigmentosum
complementation group A protein; ERCC1, excision repair
cross-complementation group 1; XPF, xeroderma pigmentosum group
F-complementing protein; XPG, xeroderma pigmentosum complementation
group G protein; MutL, mismatch repair protein complex; MutS,
mismatch recognition protein complex; Exo1, exonuclease 1; RFC,
replication factor C.

Figure 5

Metabolic reprogramming in breast
cancer and its therapeutic targets. Upregulated glycolysis,
glutamine metabolism and nucleotide synthesis sustain tumor
bioenergetics, redox balance (GSH/ROS) and DDR. Lipid metabolism
and the TCA cycle provide additional energetic support. These
adaptations drive PD-L1-mediated immune evasion and EMT, promoting
drug resistance. GSH, glutathione; ROS, reactive oxygen species;
DDR, DNA damage repair; TCA, tricarboxylic acid; PD-L1, programmed
death ligand 1; EMT, epithelial-mesenchymal transition; SLC7A11,
solute carrier family 7 member 11; ABC, ATP binding cassette; HK2,
hexokinase 2; G-6-P, glucose-6-phosphate; F-6-P,
fructose-6-phosphate; PFKFB3,
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; F-2,6-BP,
fructose-2,6-bisphosphate; PKM2, pyruvate kinase M2; PEP,
phosphoenolpyruvate; Ribose-5-P, ribose-5-phosphate; GLS,
glutaminase; PD-1, programmed cell death protein 1.
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Copy and paste a formatted citation
Spandidos Publications style
Xu W, Kang S, Xin S, Wu Y, Zhao Y and Sheng M: Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review). Oncol Rep 56: 162, 2026.
APA
Xu, W., Kang, S., Xin, S., Wu, Y., Zhao, Y., & Sheng, M. (2026). Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review). Oncology Reports, 56, 162. https://doi.org/10.3892/or.2026.9167
MLA
Xu, W., Kang, S., Xin, S., Wu, Y., Zhao, Y., Sheng, M."Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review)". Oncology Reports 56.3 (2026): 162.
Chicago
Xu, W., Kang, S., Xin, S., Wu, Y., Zhao, Y., Sheng, M."Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review)". Oncology Reports 56, no. 3 (2026): 162. https://doi.org/10.3892/or.2026.9167
Copy and paste a formatted citation
x
Spandidos Publications style
Xu W, Kang S, Xin S, Wu Y, Zhao Y and Sheng M: Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review). Oncol Rep 56: 162, 2026.
APA
Xu, W., Kang, S., Xin, S., Wu, Y., Zhao, Y., & Sheng, M. (2026). Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review). Oncology Reports, 56, 162. https://doi.org/10.3892/or.2026.9167
MLA
Xu, W., Kang, S., Xin, S., Wu, Y., Zhao, Y., Sheng, M."Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review)". Oncology Reports 56.3 (2026): 162.
Chicago
Xu, W., Kang, S., Xin, S., Wu, Y., Zhao, Y., Sheng, M."Multidimensional molecular mechanisms of drug resistance in breast cancer: Implications for clinical decision‑making and treatment strategies (Review)". Oncology Reports 56, no. 3 (2026): 162. https://doi.org/10.3892/or.2026.9167
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