Lipid Metabolism and Breast Cancer Therapy: An Integrative Literature Review.

Introduction

Lipid Metabolism Disorders and Anti-Tumor Therapy
In the latest research, breast cancer ranks second in terms of incidence rate,1 despite the emergence of an increasing number of therapeutic strategies,2,3 their efficacy remains unsatisfactory. Fatty acid metabolism is a crucial part of lipid metabolism, including ab initio synthesis, oxidation, desaturation, and elongation to different saturation levels and chain lengths. Key enzymes in fatty acid metabolism, such as ATP-citrate lyase (ACLY), fatty acid synthase (FASN), play critical roles in maintaining lipid metabolic homeostasis.4,5 Studies have shown that abnormal fatty acid metabolism is one of the hallmarks of tumorigenesis and metastasis.6 In breast cancer, the overexpression or increased activity of ACLY is associated with tumor progression.7 Down-regulating the expression of ACLY can inhibit the proliferation, invasion, and metastasis of tumor cells.8 Additionally, the expression of FASN has also been reported to be a potential therapeutic target for breast cancer brain metastasis.9
Beyond fatty acid metabolism, fatty acid β-oxidation (FAO) has been found to be associated with tumor chemoresistance, and inhibiting FAO can enhance the sensitivity of tumor cells to chemotherapy.10 Furthermore, 27-hydroxycholesterol (27-HC), a metabolite of cholesterol, can stimulate the proliferation of estrogen receptor (ER)-dependent breast cancer by acting as an estrogen receptor ligand.11 A clinical study investigating the correlation between cholesterol levels and breast cancer prognosis demonstrated that cholesterol-lowering drugs, primarily statins, can effectively reduce the recurrence risk of hormone receptor-positive (HR+) breast cancer.11,12 The above findings suggest that lipid metabolism plays an extremely important role in the development and progression of tumors.

Lipid Metabolism and Chemotherapy
The treatment of breast cancer adopts a multimodal strategy, including neoadjuvant chemotherapy, surgical treatment, radiotherapy, adjuvant chemotherapy, and endocrine therapy.13,14 Chemotherapy plays a crucial role in the treatment of breast cancer. Traditional chemotherapy regimens mainly consist of combination therapies involving alkylating agents (cyclophosphamide) and antimetabolites (methotrexate, 5-fluorouracil), which can significantly reduce the risk of recurrence.15
Recent research has shown that lipid metabolism can affect the efficacy of chemotherapy. For instance, the response and drug resistance of tumor cells to chemotherapeutic agents are associated with changes in the lipid composition of cell membranes, one of the characteristics of which is a decrease in the fluidity of the cell membrane lipid bilayer.16 Such changes can further activate membrane-bound ATP-binding cassette (ABC) multidrug efflux transporters, promoting the development of multidrug-resistant phenotypes.17,18 In contrast, regulating membrane fluidity by supplementing polyunsaturated fatty acids can alter the ABC transporter-mediated drug efflux process, suggesting that lipid modulators or dietary interventions may serve as effective strategies to overcome chemoresistance. In a Phase I clinical trial, it was found that the oral FASN inhibitor TVB-2640 could reverse the resistance of breast cancer to paclitaxel, with favorable biosafety profiles, indicating its potential clinical application value.19
Lipid droplet accumulation is another characteristic of tumor cell drug resistance.20 Compared with parental cells, drug-resistant breast cancer cells are filled with smaller but functionally normal mitochondria, as well as a large number of lipid droplets.21 Subsequent analysis of these cell lines and clinically drug-resistant breast cancer cells revealed a significant increase in the expression level of the lipid droplet-localized protein, recombinant perilipin 4 (PLIN4). Silencing PLIN4 can reduce the activity of drug-resistant cells, which suggests that targeting PLIN4 may reverse the chemoresistance of breast cancer.

Lipid Metabolism and Endocrine Therapy
Aromatase inhibitors, tamoxifen, and fulvestrant are the most commonly used therapeutic agents for estrogen receptor-positive (ER+) breast cancer. However, nearly half of breast cancer patients develop resistance to endocrine therapy, which in turn leads to tumor recurrence.22 Currently, the common mechanisms of acquired resistance in ER+ breast cancer include estrogen receptor alpha (ERα) mutation/amplification,23,24 activation of the mTOR/AKT pathway25,26 and activation of cyclin D1.26,27 In recent years, metabolic abnormalities have also been identified as another important mechanism of endocrine resistance, among which lipid metabolism is included.28,29 The mevalonate pathway is a potential pathway contributing to endocrine therapy resistance, and it is involved in the synthesis of cholesterol and isoprenoids. As a product of this pathway, increased expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is associated with enhanced tumor aggressiveness and poor prognosis.30 Sterol regulatory element-binding factor (SREBF) is a major activator of the mevalonate pathway. In tamoxifen-resistant T47D cells, the expression of genes related to SREBF activation is upregulated.20 This suggests that transcriptional reprogramming in drug-resistant breast cancer cells may be mediated through the mevalonate pathway.
Mitochondrial FAO has been confirmed to be a key metabolic pathway in triple-negative breast cancer (TNBC). Recent studies have shown that in ER+ breast cancer, metabolic reprogramming leads to increased FAO levels, which in turn induces resistance to endocrine therapy. In vitro and in vivo studies have demonstrated that targeting the rate-limiting enzyme of FAO or using FAO inhibitors can significantly enhance the sensitivity of ER+ breast cancer cells to endocrine therapy.31

Lipid Metabolism and HER-2 Targeted Therapy
The human epidermal growth factor receptor (HER/ErbB) family belongs to a class of receptor tyrosine kinases. Gene amplification of this family is observed in 20–30% of breast cancer patients, and it plays a crucial role in the initiation and progression of breast cancer.32 Patients with HER2-positive (HER2+) breast cancer are eligible for monoclonal antibody (mAb) therapy. Such drugs interfere with the function of HER2 by binding to its extracellular domain, including trastuzumab and pertuzumab.33,34
Current studies have shown that HER2+ breast cancer cells may promote their own growth through lipid metabolic reprogramming and develop resistance to HER2-targeted therapy.35,36 However, inhibiting carnitine palmitoyltransferase 1a (Cpt1a)—a key enzyme in long-chain FAO—can slow down tumor growth and enhance the efficacy of HER2-targeted therapy.37 Lipid rafts are dynamic microdomains rich in cholesterol and sphingolipids; they can participate in the signaling processes of epidermal growth factor receptor (EGFR) and HER2, thereby regulating breast cancer bone metastasis and the efficacy of HER2-targeted therapy.38 As ω-3 fatty acids, α-linolenic acid (ALA) and docosahexaenoic acid (DHA) can regulate HER2-related lipid biosynthesis phenotypes and induce cancer cell apoptosis.39 Through combined modeling and analysis of ecological phenotypes, pharmacodynamics, and metabolic parameters, it has been found that ω-3 fatty acids are potential targeted therapeutic agents for the treatment of HER2+ breast cancer.40 Therefore, adjusting nutritional intake during treatment is also a potential strategy to improve the efficacy of anti-HER2 therapeutic drugs.
In an in vitro experimental study, it was shown that the most prominent feature of breast cancer cells resistant to lapatinib is the upregulated expression of CD36—a molecule related to lipid metabolism. Moreover, HER2+ breast cancer patients with higher CD36 levels have poorer clinical prognosis. This suggests that fatty acid uptake and metabolic processes may be associated with resistance to anti-HER2 targeted therapy.35 Knocking down the CD36 gene or inhibiting CD36 expression with drugs can restore the sensitivity of lapatinib-resistant cells and induce their apoptosis; among these approaches, anti-CD36 antibodies can significantly improve the sensitivity of drug-resistant tumors to lapatinib.41

Lipid Metabolism and Immunotherapy
In breast cancer, immunotherapy is mainly applied to TNBC. TNBC does not express ER or progesterone receptor (PR), and lacks HER2 amplification, accounting for approximately 15% of all breast cancer patients.42 Compared with other breast cancer subtypes, TNBC exhibits a better response to immunotherapy, which is mainly related to three factors: first, there are more tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME);43 Second, both tumor cells and immune cells have higher levels of programmed death-ligand 1 (PD-L1) expression on their surfaces;44,45 Third, there are more nonsynonymous mutations.46 These mutations generate tumor-specific neoantigens, which in turn activate neoantigen-specific T cells and trigger an anti-tumor immune response.47
In the TME, the glycolytic pathway is suppressed, and the metabolic pattern shifts toward FAO and oxidative phosphorylation. This metabolic shift further promotes the expression of forkhead box protein P3 (FOXP3) and induces the differentiation of regulatory T cells.48 Additionally, the expression of lipid metabolism-related genes is more abundant in tumor-infiltrating regulatory T cells.49 The activation of the fatty acid synthesis (FAS) metabolic pathway in cytotoxic effector T cells can regulate the upregulated expression of key enzymes in the fatty acid synthesis pathway, such as sterol regulatory element-binding proteins (SREBPs), fatty acid synthase, and acetyl-CoA carboxylase, thereby promoting the proliferation of cytotoxic effector T cells.50 CD8+ T cells (including effector T cell subsets and memory T cell subsets) exhibit distinct lipid metabolic patterns:51,52 the hypoxic state in the TME induces a metabolic shift in effector T cells, from oxidative phosphorylation to glycolysis, resulting in increased consumption of carbohydrates and lipids; in contrast, the differentiation and functional maintenance of memory T cells mainly rely on mitochondrial FAO and oxidative phosphorylation for energy production. Lipid metabolism is highly dependent on the transcription factors SREBP1 and SREBP2, which can regulate de novo fatty acid synthesis, as well as the synthesis, uptake, and excretion of cholesterol.53 Since lipid and cholesterol are required for cell membrane synthesis, these transcription factors are crucial for the effector function of CD8+ T cells.
Tumor-associated macrophages (TAMs) play an extremely important role in mediating tumor inflammatory responses and tumor progression.54 Although the glycolytic pathway is the core pathway regulating macrophage polarization,55 Studies have shown that lipid metabolic reprogramming is of great significance for the polarization and function of TAMs.56 Promoting FAO by regulating lipid metabolism can induce the polarization of M2-type macrophages. For example, in hepatocellular carcinoma, the expression of receptor-interacting serine/threonine-protein kinase 3 (RIPK3)—a core factor of necroptosis—in macrophages is significantly downregulated, leading to a reduction in reactive oxygen species (ROS) production. This in turn activates peroxisome proliferator-activated receptors (PPARs), promotes FAO, and induces the polarization of M2-type macrophages.57
In addition to the aforementioned immune cells, tumor-associated neutrophils (TANs) can maintain the production of nicotinamide adenine dinucleotide phosphate (NADPH) and the level of reactive oxygen species (ROS) through FAO, thereby exerting immunosuppressive functions.58 Abnormal lipid metabolism can also impair the normal function of natural killer (NK) cells: the upregulated expression of lipid transporters leads to excessive fatty acid uptake by cells, activates the peroxisome proliferator-activated receptor-γ/δ (PPAR-γ/PPAR-δ) signaling pathway, and inhibits the metabolic activity of NK cells while reducing their cytotoxicity.59 Myeloid-derived suppressor cells (MDSCs) use FAO as their main energy source, with metabolic characteristics including increased fatty acid uptake, elevated mitochondrial mass, upregulated expression of key enzymes in the oxidative phosphorylation pathway, and increased oxygen consumption. Knocking out CD36 or inhibiting FAO can disrupt the immunosuppressive function of MDSCs, thereby improving the efficacy of immunotherapy and delaying tumor progression.60

Lipid Metabolism and Small Molecule Inhibitors
Combination therapy with cyclin D-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy is the standard treatment regimen for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer.61–63 The combination of the two can further enhance the effect of cell cycle arrest.64 Despite the certain efficacy achieved by this type of treatment, the vast majority of patients still experience disease progression in the advanced stage, and many patients still suffer from recurrence even after receiving adjuvant therapy. Therefore, there is an urgent need for new therapeutic strategies to overcome drug resistance and improve treatment sensitivity.
Alpelisib is a PI3Kα-specific inhibitor available in combination with fulvestrant for patients with PIK3CA mutations after prior ET. In the randomized Phase III SOLAR-1 trial, the addition of alpelisib to fulvestrant significantly improved PFS, with a trend towards improved OS in patients with PIK3CA-mutated tumors (detected in exons 9 or 20, in tumor tissue or circulating tumor DNA).65,66 Another option is the mTOR inhibitor everolimus, which is offered in combination with exemestane to patients with (ER+/HER2-) breast cancer who have progressed during or after treatment with an NSAID AI prior to or after treatment with fulvestrant because of a significant improvement in PFS, but not OS, compared to exemestane alone.67 Histone deacetylase (HDAC) inhibitors are another option for patients with HR-positive advanced breast cancer who have progressed after prior ET.68 Of these, HDACi is most closely related to lipid metabolism. Short-chain fatty acids are able to mediate anticancer effects by inhibiting HDAC activity. Recent studies have identified odd-chain fatty acids as novel HDACi.69 And recent studies have shown that cholesterol supplementation attenuates the therapeutic effects of CDK4/6i.70 However, there are fewer relevant studies, which deserve further in-depth investigation.

Conclusion
Due to the specificity of the TME infiltrated by adipocytes surrounding breast cancer, an increasing number of studies have recognized that lipid metabolism is associated with acquired resistance to a variety of anti-breast cancer drugs. Recent studies have shown that combination therapeutic strategies targeting lipid metabolism may be a viable approach to overcome drug resistance in the future. Therefore, we believe that the use of tumor genomic and lipidomic assays, combined with the classification of fatty acids in tumor cells, the microenvironment, and the daily diet, to design a more comprehensive precision medicine strategy will be the way forward to improve the prognosis of breast cancer patients.