Nhi Ho

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with poor prognosis, early recurrence, and increased metastatic spread.^1,2 TN tumors lack estrogen receptor, progesterone receptor, and HER2 expression, limiting hormonal and HER2-directed therapies.^1,2 Obesity is a well-established breast cancer risk factor that worsens TNBC outcomes.¹ In obese mammary environment, chronic inflammation, altered adipose-immune interactions, and epigenetic remodeling shift the breast toward a pro-tumor state that promotes stem-like, invasive, and treatment-resistant phenotypes.^1,3 These changes overlap with downstream effects of Wnt/β-catenin pathway activation, which drives proliferation, invasion, and metastasis.^1,2 SFRP1, a secreted Wnt antagonist, blocks Wnt–Frizzled binding, and its loss permits sustained β-catenin activation.^1,2,4 However, the mechanisms by which obesity converges to promote TNBC progression remain incompletely defined.

Objective: In this literature review, the mechanisms by which obesity activates β-catenin signaling to promote TNBC progression, with particular focus on the role of SFRP1 loss as a central mechanistic node was examined.

Search Methods: A search of the PubMed database was conducted for articles published between 2018 and 2026 using the keywords: “triple-negative breast cancer,” “obesity,” “Wnt/β-catenin,” “SFRP1,” “DNA methylation,” and “adipose tissue macrophages.”

Results: Compared to lean controls on a low-fat diet, mice with diet-induced obesity displayed extensive mammary remodeling, including 3,311 differentially expressed genes and 6,693 differentially methylated regions, with enrichment of epithelial-mesenchymal transition (EMT), hypoxia, reactive oxygen species (ROS), and p53-related pathways. Dietary restriction reduced orthotopically implanted TNBC tumor mass, lung micrometastases, and systemic inflammation.⁴ Mammary adipose tissue macrophages from obese mice adopted a pro-inflammatory program that expanded the CD90⁺CD24⁺ tumor-initiating population and increased tumorsphere formation, with IL-6 in conditioned media rising ~two-fold. Blocking the IL-6/GP130 axis reduced STAT3 phosphorylation, stemness markers (Sox2, Oct4, Nanog), and tumor initiation. 4-day nutrient excess did not reproduce these effects, while weight loss reversed the phenotype.⁵ Tumor-intrinsic loss of the zinc-finger transcription factor ZNF334, identified by promoter methylation in 71.88% (46/64) of breast tumors, lowered SFRP1 and increased active β-catenin, c-Myc, and cyclin D1, promoting proliferation and invasion. ZNF334 re-expression restored SFRP1 and suppressed Wnt reporter activity, colony formation, xenograft growth, migration, invasion, EMT, and stemness. SFRP1 knockdown reversed these effects.⁶ A second route to SFRP1 loss involved DNMT1/DNMT3A-mediated methylation of the SFRP1 promoter. DNMT knockdown or nimbolide nanoparticle treatment restored SFRP1, suppressed Wnt/β-catenin signaling, and reduced stemness, EMT, and chemoresistance.⁷

Conclusions: Obesity drives TNBC progression through convergent inflammatory and epigenetic mechanisms that activate Wnt/β-catenin signaling, with SFRP1 loss serving as a central mechanistic node. ZNF334 disruption and DNMT-mediated promoter methylation provide two complementary routes to SFRP1 silencing,^6,7 while obesity-associated mammary macrophage IL-6/GP130 signaling further reinforces β-catenin-driven stemness, invasion, and chemoresistance.⁵ Lifestyle intervention through dietary restriction and weight loss partially reverses these pro-tumorigenic obesity-associated effects,^4,5 and multiple pathway components (IL-6/GP130, DNMTs, and Wnt/β-catenin) represent potential targets for prevention-oriented or combination therapeutic strategies in obesity-associated TNBC.

Works Cited:

1. Donovan MG, Wren SN, Cenker M, Selmin OI, Romagnolo DF. Dietary fat and obesity as modulators of breast cancer risk: Focus on DNA methylation. Br J Pharmacol. 2020;177(6):1331-1350. doi:10.1111/bph.14891
2. Sharma A, Mir R, Galande S. Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer. Front Genet. 2021;12:681053. doi:10.3389/fgene.2021.681053
3. Maleknia M, Ahmadirad N, Golab F, Katebi Y, Haj Mohamad Ebrahim Ketabforoush A. DNA Methylation in Cancer: Epigenetic View of Dietary and Lifestyle Factors. Epigenetic Insights. 2023;16. doi:10.1177/25168657231199893
4. Bowers LW, Doerstling SS, Shamsunder MG, et al. Reversing the Genomic, Epigenetic, and Triple-Negative Breast Cancer–Enhancing Effects of Obesity. Cancer Prev Res (Phila). 2022;15(9):581-594. doi:10.1158/1940-6207.CAPR-22-0113
5. Tiwari P, Blank A, Cui C, et al. Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer. J Exp Med. 2019;216(6):1345-1358. doi:10.1084/jem.20181616
6. Cheng Z, Yu R, Li L, et al. Disruption of ZNF334 promotes triple-negative breast carcinoma malignancy through the SFRP1/Wnt/β-catenin signaling axis. Cell Mol Life Sci. 2022;79:280. doi:10.1007/s00018-022-04295-1
7. Mohapatra P, Madhulika S, Behera S, et al. Nimbolide-based nanomedicine inhibits breast cancer stem-like cells by epigenetic reprogramming of DNMTs–SFRP1–Wnt/β-catenin signaling axis. Mol Ther Nucleic Acids. 2023;34:102031. doi:10.1016/j.omtn.2023.102031