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Several of the best-described signaling pathways influencing self-renewal and differentiation in mature stem cells, like Wnt/β-catenin, Notch, Hedgehog and TGF-β/BMP pathways are commonly regulated in cancer via epigenetic processes [91]. |
Abnormal epigenetic changes in ADH could restart developmental paths, for example Notch signaling and Wnt/β-catenin signaling, that are usually suppressed in mature cells but are reactivated through cancer development [91,93]. |
Notch signaling controls cell multiplication, differentiation and influences cell outcome and programmed cell death [93]. Notch signaling is controlled via Notch receptors (1–4) and ligands for instance Delta-like ligand (DDL 1/3/4) and Jagged 1/2 [124]. Notch signaling collaborates with transcription factors of EMT (S... |
Wnt signaling pathway, which regulates the expression of target genes via β-catenin, represents a key mechanism of stem cells and CSCs and is abnormally activated through the growth of several human cancers [93]. Acquisition of function mutations of the CTNNB1 gene (encoding β-catenin) and deficit-of-function mutations... |
Hedgehog (Hh) signaling modulates the proliferation of stem and precursor cells in several tissues, and alterations in this pathway have been implicated in tumor growth [93,132]. Hh signaling pathway cooperates with Wnt-β-catenin signaling, inducing tumorigenesis and cancer severity [133]. This mechanism could regulate... |
BMP/TGF-β signaling pathways control numerous biological processes like proliferation, differentiation, and programmed cell death [91]. Deregulating the molecular effectors of TGF-β signaling could lead to cancer [93]. TGF-β functions as a tumor suppressor in tumor induction. The initial phases of tumor development and... |
### 5.3. Epigenetic Plasticity |
Epigenetic plasticity enables cells to dynamically alter gene expression patterns in response to the evolving TME, facilitating adaptation and survival under stressful conditions such as hypoxia or nutrient scarcity. This adaptability also allows cancer cells to circumvent intrinsic cellular checkpoints that typically ... |
These epigenetic alterations can become heritably fixed through successive cell divisions, stabilizing a malignant phenotype that supports sustained tumor growth. In the context of breast cancer, such changes drive progression from premalignant lesions like ADH by repressing tumor suppressor genes (e.g., via hypermethy... |
Table 3 highlights some known epigenetic alterations in different hyperplasia subtypes, while Table 4 provides more details on the molecular and cellular effects. |
[TABLE] Notable epigenetic changes in mammary ductal hyperplasia (MDH) subtypes. |
Lesion Type/Stage | Epigenetic Alterations |
Early proliferative lesions (UDH, mild hyperplasia) | Subtle epigenetic deviations may begin. Global DNA methylation levels start to increase in proliferative breast tissue. Promoter methylation is generally low in UDH, but isolated foci can show initial methylation of genes like RASSF1A. Histones in UDH largely retain... |
Atypical hyperplasias (ADH, ALH, FEA) | Promoter hypermethylation becomes common and non-random. Frequent methylation of tumor suppressor genes (e.g., RASSF1A, APC) is documented in ADH and FEA lesions. In lobular neoplasia, CDH1 promoter methylation is an alternative mechanism to gene mutation for turning off E-cadher... |
Carcinoma in situ (DCIS, LCIS) | Widespread epigenetic reprogramming is present. DCIS lesions show hypermethylation at numerous loci, e.g., more than 40% of DCIS cases have RASSF1A gene methylation [68], and many harbor methylation of p16, cyclin D2, and others. LCIS (especially pleomorphic LCIS) likewise accumulates m... |
[TABLE] Molecular and cellular effects of epigenetic mechanisms driving malignancy in atypical hyperplasia. |
Mechanism | Gene Targets/Factor | Molecular Results in ADH/DCIS | Functional Consequences |
Promoter hypermethylation (DNA) | RASSF1, CDKN2A (p16INK4a), BRCA1, PTEN | Stable silencing of tumor suppressors | Loss of cell cycle arrest; early event in monoclonal progression [142] |
Oncogene hypomethylation (DNA) | HER2, CCND1 (Cyclin D1) | Transcriptional increase | Overexpression of proliferation drivers [143] |
Non-coding RNA dysregulation | miR-21 (Upregulation) | Post-transcriptional inhibition of PTEN | Constitutive activation of the PI3K/AKT pathway; promotes survival [144] |
Histone modifications/remodeling | KMT2C/D, EZH2 | Aberrant acetylation/methylation patterns | Transcriptional reprogramming for malignant phenotype [47] |
## 6. Tumor Microenvironment Changes in Driving Malignant Transformation of Atypical Hyperplasia |
The TME in breast ADH encompasses a multifaceted, evolving landscape comprising neoplastic epithelial cells, stromal fibroblasts, immune cells, vascular networks, and extracellular matrix (ECM) components. These components interact synergistically to modulate the progression from premalignant states, such as ADH, to DC... |
### 6.1. Key TME Components and Their Impact on Malignant Transformation |
#### 6.1.1. Stromal Remodeling |
Remodeling in ADH involves the activation and phenotypic shift in fibroblasts, leading to desmoplasia and a supportive niche for epithelial proliferation and invasion. Histopathologically, early ADH exhibits periductal fibrosis with an increased density of α-SMA-positive CAFs, which are observable on IHC as spindle-sha... |
This stromal-epithelial crosstalk is evident in vivo, where high HGF expression in the stromal compartment correlates with basal-like subtypes and poorer survival, highlighting stromal contributions to ADH malignant transformation. Furthermore, myoepithelial cells in ADH undergo phenotypic alterations, as indicated by ... |
#### 6.1.2. Immune Cell Infiltration |
The immune landscape in ADH’s TME features progressive infiltration of lymphocytes and macrophages, which can either suppress or promote malignant transformation depending on their phenotype and spatial distribution [150]. Histopathologically, H-E staining of ADH biopsies reveals periductal lymphocytic aggregates, with... |
In hypoxic conditions, myeloid cells release S100A9, which fosters systemic immunosuppression, as evidenced by altered CD4+/CD8+ ratios in lymphoid organs and reduced T cell proliferation in cocultures [152]. Histologically, ADH progressing to DCIS shows enhanced stromal immune infiltrates, including macrophages, on H&... |
#### 6.1.3. Hypoxia and Angiogenesis |
Hypoxic niches in expanding ADH lesions trigger angiogenesis, providing sustenance for proliferation and invasion. Histopathologically, central necrosis in atypical ducts on HE signals hypoxia, with IHC showing nuclear hypoxia-inducible factor-1α (HIF-1α) stabilization in epithelial and stromal cells. This induces vasc... |
Angiogenesis precedes significant stromagenesis in ADH, as evidenced by VEGF-positive epithelial cells and immature vessels on IHC, fostering a permissive environment for invasion. |
In obesity contexts, HFD exacerbates hypoxic signaling, accelerating angiogenic changes in ADH, while weight loss mitigates this via kinase modulation, reducing vascular support for progression [157]. HGF/MET pathways also contribute, with upregulated signaling in ADH, leading to tortuous vessels observable in 3D model... |
#### 6.1.4. Extracellular Matrix (ECM) and Cell–Cell Interactions |
ECM remodeling in ADH disrupts the structural integrity of the epithelium, enabling epithelial invasion. Histopathologically, Masson’s trichrome staining reveals disorganized collagen in periductal stroma, with IHC showing elevated MMPs from activated fibroblasts degrading basement membranes. Basement membrane disconti... |
Cell–cell adhesions weaken, with IHC demonstrating E-cadherin loss and CEACAM1 redistribution from apical to cytoplasmic patterns in progressing ADH (p < 0.05), driven by Id-1 overexpression. In 3D cultures, HGF/MET activation induces morphological shifts, such as epithelial budding and ECM invasion, reversible by sign... |
#### 6.1.5. Exosomes and Tumor Signaling |
Exosomes in ADH’s TME mediate intercellular signaling, transferring oncogenic cargo to remodel the niche. Although direct visualization is challenging, indirect evidence from IHC indicates exosome-driven alterations, such as nuclear accumulation of HIF-1α in recipient cells [129]. Hypoxic sEVs from premalignant cells i... |
In conclusion, the histopathological evolution of the TME in ADH—encompassing stromal activation, immune shifts, hypoxic angiogenesis, ECM degradation, and exosomal communication—critically drives malignant transformation. Integrated analyses from IHC, imaging, and molecular profiling provide robust evidence for these ... |
## 7. Diet and Environmental Factors Influencing the Transformation of Atypical Ductal Hyperplasia (ADH) into Breast Cancer |
### 7.1. Dietary Factors Influencing ADH Progression |
According to the American Cancer Society, about 30% of the breast cancers in postmenopausal patients are related to modifiable risk factors, including diet [163]. Moreover, some research suggests that a healthy diet could prevent breast cancer onset, improve therapeutic outcome and decrease the risk of recurrence among... |
High-fat diet is an important risk factor for the onset and progression of breast cancer, through multiple pathogenetic mechanisms, involving increased systemic inflammation and oxidative stress [165]. Increased intake of total and saturated animal fat, found in red meat and high-fat dairy, was linked to the risk of br... |
A high-fat diet can disrupt the gut microbiota, increasing the risk of malignancies, by the activation of the “gut-bone marrow-tumor” axis. Altered microbiota can produce large amounts of leucine, capable of activating the mTORC1 signaling in myeloid progenitor cells, resulting in differentiation of polymorphonuclear m... |
High-fat diets may promote tumor cell metastasis by preactivating platelets and endothelial cells and by forming premetastatic niches. Within niches, the crosstalk between activated platelets, endothelial cells and cancer cells promotes metastasis [170]. |
Additionally, high-fat diets are a major driver of obesity, which itself increases breast cancer risk and progression through complex signaling pathways affecting cell growth and angiogenesis [171]. |
Obesity is a high-risk factor for breast cancer and poor prognosis in women after menopause [172]. Moreover, the risk of triple-negative breast cancer and mortality post diagnosis is significantly increased in both pre- and postmenopausal obese women, compared with normal-weight women [173]. |
Potential pathogenic mechanisms underlying these associations include: increased estrogen levels, dysregulated insulin and Insulin-like growth factor (IGF) signaling, altered adipokines released by adipose cells, and chronic systemic inflammation indicated by high levels of C-reactive protein [41,174]. |
In postmenopausal women, the link between obesity and high estrogen levels is more significant, since, after menopause, the adipose tissue is the main source of estrogen. Excess estrogen derived from androgen aromatization in the adipose tissue, associated with obesity-related decrease in sex hormone binding globulin c... |
Imbalance in adipokines due to increased mass of adipose tissue is also responsible for direct activation of breast cancer cells, contributing to tumor growth and invasion. Low adiponectin levels and high leptin levels were linked to poor prognosis of breast cancer. Adiponectin has a protective role by inhibiting cance... |
Chronic systemic inflammation maintains a pro-inflammatory state in adipose tissue, leading to increased secretion of inflammatory cytokines that promote tumor progression and metastasis. In obese individuals, adipose tissue is infiltrated by numerous macrophages, which form crown-like structures surrounding degenerati... |
NF-κB, expressed in human breast cancer tumor cells, supports cancer cells’ survival and differentiation into an aggressive phenotype, and is also responsible for the ET resistance in ER+ breast tumors [184]. Expression of HIF-1α in adipose tissue macrophages has been detected in patients with insulin resistance and al... |
PI3K-AKT-mTOR pathway controls cell growth and survival and has been demonstrated to cross-talk with estrogen receptor (ER) pathway; thus, alterations of PI3K-AKT-mTOR pathway are present in ER+ breast cancer [186]. |
Insulin resistance, which often accompanies obesity, leads to elevated levels of insulin and IGF, known as potent mitogens. Insulin and IGF-related tumorigenesis occurs by activation of oncogenic pathways such as PI3K/Ras-Raf in the affected cells, resulting in cell proliferation and ADH progression [187]. |
According to data published by the World Cancer Research Fund, a higher risk of breast cancer is linked to alcohol consumption, even in low amounts. Pathogenic mechanisms underlying the association between ethanol intake and mammary tumorigenesis include: oxidative stress by accumulation of reactive oxygen species (ROS... |
Reducing high-fat foods, especially processed meats, fried goods, and high-fat dairy, and replacing them with unsaturated fats, fruits, vegetables, and the correct supplementation with vitamins and minerals is a key lifestyle recommendation for breast cancer prevention and outcome management [142]. |
Phytoestrogens are plant-derived compounds found in various foods: fruits, vegetables, grains, legumes such as soybeans, flaxseeds, tofu, and lentils [190]. Due to their molecular structure, these compounds perform a wide range of pharmacologic effects, acting as antioxidants, anti-inflammatories, anti-tumoral agents, ... |
Vitamins can also have anti-cancer properties. Studies suggest that vitamin D may inhibit tumor cell proliferation in mammary hyperplastic lesions, whereas vitamins C, E, and carotenoids exert antioxidant properties [194]. Dietary fibers are beneficial for breast cancer prevention by reducing glucose absorption and gly... |
### 7.2. Environmental Factors and Toxins Influencing ADH Progression |
Although ADH already reflects a significant factor for the malignant transformation, other environmental and toxic factors such as endocrine disruptor chemicals, air pollution, pesticides, radiation exposure, etc., may have an important role in how ADH lesions evolve [196]. |
#### 7.2.1. Ionizing Radiations |
One of the most powerful environmental factors influencing ADH Progression is ionizing radiation, which directly induces double-stranded DNA breaks and also, in mammary epithelial cells, chromosomal instability. Studies show that even low doses of radiation can cause the activation of DNA repair and cell cycle genes (e... |
Studies in mice have suggested that radiation exposure causes the activation of genes that are involved in proliferative and metabolic pathways that play a role in carcinogenesis in the mammary glands [198]. |
#### 7.2.2. Chemical Endocrine Disruptors |
Endocrine disruptors are natural or synthetic substances that are able to affect the physiological functions of the endocrine system [199]. These chemicals (EDCs) represent a class of anthropogenic compounds (e.g., bisphenol A, phthalates, and perfluoroalkyl substances) that mimic or antagonize natural hormones. Low-do... |
Bisphenol A (BPA) is used to produce polycarbonate plastics (e.g., plastic bottles), and recent studies discovered that exposure to BPA, due to the ability to mimic estrogen, can increase the growth of cancer cells in the breast [201]. |
#### 7.2.3. Air Pollution |
Airborne pollutants and particulate matter (PM) contain a multitude of compounds such as polycyclic aromatic hydrocarbons (PAHs) and metals which can stimulate the progression of mammary cancer [202]. |
Exposure to PM2.5 can lead to oxidative damage to the DNA and can also increase the expression level of oxidation markers. Cellular responses to these factors are activation of transcription factors, release of inflammatory mediators, etc., which can lead to cellular apoptosis. Studies revealed that urban residents hav... |
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and are formed in the organic fuel combustion process. Studies have correlated PAH exposure with development of breast cancer [204]. |
#### 7.2.4. Pesticides |
Pesticides such as organophosphates, organochlorines and fungicides have been proven to increase the risk of breast cancer [205]. Organophosphates, a class of chemicals used as pesticides, are proven to act as endocrine disruptors and can increase the risk of mammary tumor development [206]. |
Dichlorodiphenyltrichloroethane (DDT), a synthetic organochlorine, is found to be in the adipose tissue and studies revealed that higher levels of DDT was found in women with breast cancer compared to women without cancer and a lower DDT level [207]. |
#### 7.2.5. General Indications |
Lifestyle modifications like weight control and limiting environmental toxin exposure vary in effectiveness for reducing progression from atypical ductal hyperplasia (ADH) to breast cancer in specific populations. In postmenopausal women at higher risk from adipose-derived estrogen, weight management via calorie restri... |
## 8. Conclusions |
This review has examined the complex spectrum of MDH and its potential role as a precursor to breast cancer, highlighting why certain subtypes, especially those with atypia, pose a higher risk of becoming malignant. By combining epidemiologic, histopathologic, molecular, and environmental data, we have emphasized the m... |
Stratified risk assessments enable targeted monitoring: women with atypical hyperplasia might benefit from increased mammographic screening, chemoprevention, or preventive procedures, while women with non-atypical lesions need routine surveillance. Lifestyle changes, such as weight management and reduced toxin exposure... |
## Abbreviations |
The following abbreviations are used in this manuscript: |
[TABLE] |
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