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Cell Reports Jan 2024Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary...
Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoiding breast cancer development. Here, we show that lactogenic differentiation of murine MECs requires silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcript PAPAS. Accordingly, knockdown of PAPAS derepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. Restoring PAPAS levels in breast cancer cells reduces tumorigenicity and lung invasion and activates many interferon-regulated genes previously linked to metastasis suppression. Mechanistically, PAPAS transcription depends on R-loop formation at the 3' end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion of PAPAS and upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.
Topics: Pregnancy; Female; Mice; Animals; Humans; Mammary Glands, Animal; Breast; Cell Differentiation; Breast Neoplasms; Cell Transformation, Neoplastic; Epithelial Cells
PubMed: 38180837
DOI: 10.1016/j.celrep.2023.113644 -
Bladder (San Francisco, Calif.) 2023Bladder cancer is among the most lethal urinary system cancers across the globe. Macrophage 1 and Macrophage 2 play an essential role in the pathogenesis of tumors....
BACKGROUND
Bladder cancer is among the most lethal urinary system cancers across the globe. Macrophage 1 and Macrophage 2 play an essential role in the pathogenesis of tumors. Nevertheless, prior studies failed to investigate the implication of the two cells, working in combination, in the development, growth, progression and metastasis of bladder cancer.
METHODS
We computed the M1/M2 ratio of the samples retrieved from The Cancer Genome Atlas (TCGA) by using the Cibersortx algorithm and calculated the ratio in 32 patients in our series by employing flow cytometry. SurvivalRandomForest was utilized to reduce the dimension of the list of the M1/M2-related genes, with an aim to obtain the most survival-predictive gene () encoding epithelial membrane protein 1 (EMP1). The EMP1 was biologically characterized by using Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and Gene Ontology (GO). The single-cell transcriptome (sc-RNA) analysis was then applied to further look into the function of . Finally, Cellchat was employed to examine the interaction between macrophages and epithelium cells.
RESULTS
The results showed that higher M1/M2 ratio was found to be associated with a more favorable prognosis of bladder cancer. was identified to be the key gene indicative of M1/M2 ratio and higher expression was associated with poor prognosis. Further analyses showed that might promote tumor invasion and metastasis via epithelial-mesenchymal transition (EMT) and focal adhesion (FA). Moreover, the expression level of could serve as an indicator of immunotherapy efficacy. The scRNA-seq data indicated that in cancer cells was strongly associated with tumor proliferation. Finally, the Cellchat results exhibited that might promote the interaction between macrophages and cancer cells through the fibronectin 1-syndecan 1 (FN1-SDC1) pathway.
CONCLUSION
Our study identified , an M1/M2-related gene, the expression of which may act as a prognostic indicator for the proliferation, metastasis, and response to immunotherapy. might be involved in the regulation on M1/M2 ratio.
PubMed: 38163006
DOI: 10.14440/bladder.2023.852 -
The Journal of Investigative Dermatology Jun 2024The Wnt/β-catenin pathway plays a critical role in cell fate specification, morphogenesis, and stem cell activation across diverse tissues, including the skin. In...
The Wnt/β-catenin pathway plays a critical role in cell fate specification, morphogenesis, and stem cell activation across diverse tissues, including the skin. In mammals, the embryonic surface epithelium gives rise to the epidermis as well as the associated appendages including hair follicles and mammary glands, both of which depend on epithelial Wnt/β-catenin activity for initiation of their development. Later on, Wnts are thought to enhance mammary gland growth and branching, whereas in hair follicles, they are essential for hair shaft formation. In this study, we report a strong downregulation of epithelial Wnt/β-catenin activity as the mammary bud progresses to branching. We show that forced activation of epithelial β-catenin severely compromises embryonic mammary gland branching. However, the phenotype of conditional Lef1-deficient embryos implies that a low level of Wnt/β-catenin activity is necessary for mammary cell survival. Transcriptomic profiling suggests that sustained high β-catenin activity leads to maintenance of mammary bud gene signature at the expense of outgrowth/branching gene signature. In addition, it leads to upregulation of epidermal differentiation genes. Strikingly, we find a partial switch to hair follicle fate early on upon stabilization of β-catenin, suggesting that the level of epithelial Wnt/β-catenin signaling activity may contribute to the choice between skin appendage identities.
Topics: Animals; beta Catenin; Mice; Mammary Glands, Animal; Morphogenesis; Female; Wnt Signaling Pathway; Cell Differentiation; Hair Follicle; Lymphoid Enhancer-Binding Factor 1; Epithelial Cells; Gene Expression Regulation, Developmental
PubMed: 38159590
DOI: 10.1016/j.jid.2023.11.018 -
Cureus Nov 2023A 64-year-old woman presented to our institution with a palpable and painful left breast mass. She denied any other breast symptoms. Subsequent imaging classified it as...
A 64-year-old woman presented to our institution with a palpable and painful left breast mass. She denied any other breast symptoms. Subsequent imaging classified it as a US Breast Imaging-Reporting and Data System (BI-RADS) 4A lesion. A core needle biopsy was performed showing atypical proliferating fragments of squamous epithelium suspicious for malignant neoplasm. An excisional biopsy was recommended. Gross examination showed a well-circumscribed pink soft mass measuring 2.0 x 1.4 x 1.3 cm. The entire lesion was submitted for histologic evaluation, demonstrating a neoplasm with branching stroma and exuberant squamous differentiation. The lesion exhibited obvious cytologic features of malignancy like mitotic figures, prominent nucleoli, irregular nuclei, and multinucleation. Collagen IV stain ruled out invasion. The lesion was finally classified as squamous cell carcinoma (SCC) in situ with the configuration of an intraductal papilloma. The possibility of metastatic disease was suggested. A PET scan was negative, and no other foci of disease were found in the remainder of the specimen. The mass was also independent of nipple and skin. Based on the architectural features, we believe that this is a case of an intraductal papilloma that underwent complete squamous metaplasia with no residual adenomyoepithelial components and transformation into an SCC in situ demonstrated by stains. Papillomas can undergo reactive metaplastic changes, usually benign and in small foci. This is the first reported case of exuberant squamous epithelium that transformed into carcinoma in situ with papillary architecture in the breast.
PubMed: 38146557
DOI: 10.7759/cureus.49382 -
Frontiers in Oncology 2023Epithelial-mesenchymal transition (EMT) is a cellular plasticity program critical for embryonic development and tissue regeneration, and aberrant EMT is associated with...
Epithelial-mesenchymal transition (EMT) is a cellular plasticity program critical for embryonic development and tissue regeneration, and aberrant EMT is associated with disease including cancer. The high degree of plasticity in the mammary epithelium is reflected in extensive heterogeneity among breast cancers. Here, we have analyzed RNA-sequencing data from three different mammary epithelial cell line-derived EMT models and identified a robust mammary EMT gene expression signature that separates breast cancers into distinct subgroups. Most strikingly, the basal-like breast cancers form two subgroups displaying partial-EMT and post-EMT gene expression patterns. We present evidence that key EMT-associated transcription factors play distinct roles at different stages of EMT in mammary epithelial cells.
PubMed: 38111531
DOI: 10.3389/fonc.2023.1249895 -
Breast Cancer : Basic and Clinical... 2023Metaplastic breast carcinoma is an invasive carcinoma with a high differentiation rate of the neoplastic epithelium toward mesenchymal-like epithelium. It comprises of...
Metaplastic breast carcinoma is an invasive carcinoma with a high differentiation rate of the neoplastic epithelium toward mesenchymal-like epithelium. It comprises of only less than 1% of all breast cancers. Although 80% to 90% of metaplastic breast carcinomas are triple-negative cancers, they usually have worse outcomes than other triple-negative breast cancers (TNBCs). Metaplastic carcinoma is also often refractory to cytotoxic chemotherapy. Here, we reported a case of a 61-year-old female patient, presenting with a solitary and pedunculated mass in the right axillary tail breast tissue, whose biopsy revealed metaplastic breast carcinoma with chondroid differentiation. She had failed neoadjuvant chemotherapy and immunotherapy. Although she received debulking surgery, the tumor regrew even faster before surgery. Despite receiving palliative chemotherapy, the patient died 11 weeks after surgery. This case draws attention to physicians that early recognition and surgery may be more beneficial than chemotherapy in combating metaplastic breast carcinoma.
PubMed: 38024140
DOI: 10.1177/11782234231215183 -
Cureus Oct 2023A cutaneous horn, referred to as a cornu cutaneum in Latin, presents as a mound of keratinizing epithelium. The etiology of the cutaneous horn is associated with the...
Cornu Cutaneum: Case Reports of Patients With a Cutaneous Horn Associated With Either a Verruca Vulgaris or an Inverted Follicular Keratosis and a Review of the Etiologies of Cutaneous Horns.
A cutaneous horn, referred to as a cornu cutaneum in Latin, presents as a mound of keratinizing epithelium. The etiology of the cutaneous horn is associated with the lesion at its base. In addition to numerous benign and malignant neoplasms, cutaneous horns may be related to infections and skin conditions. The features of a 22-year-old woman with a cutaneous horn associated with a recalcitrant verruca vulgaris on her left fifth toe are described. In addition, the characteristics of a 57-year-old man with an inverted follicular keratosis-related cutaneous horn on his upper lip are reported. In order of decreasing frequency, a cutaneous horn is most associated with either an actinic keratosis (25%), a squamous cell carcinoma (19%), a seborrheic keratosis (19%-20%), or a verruca vulgaris (18%). Adnexal neoplasms, epithelial lesions, fibrous lesions, granular cell tumors, hamartomas, histiocytic lesions, melanocytic nevus, premalignant keratoses, a subungual lesion, and vascular lesions comprise the benign neoplasms that have been observed at the base of a cutaneous horn. Dermatologic conditions that have been associated with a cutaneous horn include discoid lupus erythematosus (three patients) and one patient with either palmoplantar keratoderma, psoriasis, or sarcoidosis. Human papillomavirus infection presenting as a verruca vulgaris is the most commonly associated infection; pox virus-related molluscum contagiosum is another viral infection that is less often observed associated with a cutaneous horn. Leishmaniasis, rhinosporidiosis, and cutaneous tuberculosis are rare cutaneous horn-related infections. A malignant tumor-associated cutaneous horn is most frequently caused by squamous cell carcinoma; other less common cancers include basal cell carcinoma, sebaceous carcinoma, verrucous carcinoma, and malignant melanoma. A cancer-related cutaneous horn has only been described in two patients with Kaposi sarcoma and one patient with either Merkel cell carcinoma or Paget disease of the breast or metastatic renal cell carcinoma. In summary, a cutaneous horn is potentially related to a tumor, an infection, or a skin disorder; an adequate evaluation of the base of the cutaneous horn is usually required to establish the associated diagnosis.
PubMed: 38022343
DOI: 10.7759/cureus.46747 -
Cell Genomics Nov 2023Although lineage-specific genes have been identified in the mammary gland, little is known about the contribution of the 3D genome organization to gene regulation in the...
Although lineage-specific genes have been identified in the mammary gland, little is known about the contribution of the 3D genome organization to gene regulation in the epithelium. Here, we describe the chromatin landscape of the three major epithelial subsets through integration of long- and short-range chromatin interactions, accessibility, histone modifications, and gene expression. While basal genes display exquisite lineage specificity via distal enhancers, luminal-specific genes show widespread promoter priming in basal cells. Cell specificity in luminal progenitors is largely mediated through extensive chromatin interactions with super-enhancers in gene-body regions in addition to interactions with polycomb silencer elements. Moreover, lineage-specific transcription factors appear to be controlled through cell-specific chromatin interactivity. Finally, chromatin accessibility rather than interactivity emerged as a defining feature of the activation of quiescent basal stem cells. This work provides a comprehensive resource for understanding the role of higher-order chromatin interactions in cell-fate specification and differentiation in the adult mouse mammary gland.
PubMed: 38020976
DOI: 10.1016/j.xgen.2023.100424 -
Differentiation; Research in Biological... Nov 2023Fibroblast growth factor 20 (FGF20) is a neurotrophic factor and a member of the FGF9 subfamily. It was first identified in Xenopus embryos and was isolated shortly...
Fibroblast growth factor 20 (FGF20) is a neurotrophic factor and a member of the FGF9 subfamily. It was first identified in Xenopus embryos and was isolated shortly thereafter from the adult rat brain. Its receptors include FGFR4, FGFR3b, FGFR2b and the FGFRc splice forms. In adults it is highly expressed in the brain, while it is expressed in a variety of regions during embryonic development, including the inner ear, heart, hair placodes, mammary buds, dental epithelium and limbs. As a result of its wide-spread expression, FGF20 mouse mutants exhibit a variety of phenotypes including congenital deafness, lack of hair, small kidneys and delayed mammary ductal outgrowth. FGF20 is also associated with human diseases including Parkinson's Disease, cancer and hereditary deafness.
PubMed: 38007375
DOI: 10.1016/j.diff.2023.10.005 -
Particle and Fibre Toxicology Nov 2023Perinatal exposure to titanium dioxide (TiO), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel...
BACKGROUND
Perinatal exposure to titanium dioxide (TiO), as a foodborne particle, may influence the intestinal barrier function and the susceptibility to develop inflammatory bowel disease (IBD) later in life. Here, we investigate the impact of perinatal foodborne TiO exposure on the intestinal mucosal function and the susceptibility to develop IBD-associated colitis. Pregnant and lactating mother mice were exposed to TiO until pups weaning and the gut microbiota and intestinal barrier function of their offspring was assessed at day 30 post-birth (weaning) and at adult age (50 days). Epigenetic marks was studied by DNA methylation profile measuring the level of 5-methyl-2'-deoxycytosine (5-Me-dC) in DNA from colic epithelial cells. The susceptibility to develop IBD has been monitored using dextran-sulfate sodium (DSS)-induced colitis model. Germ-free mice were used to define whether microbial transfer influence the mucosal homeostasis and subsequent exacerbation of DSS-induced colitis.
RESULTS
In pregnant and lactating mice, foodborne TiO was able to translocate across the host barriers including gut, placenta and mammary gland to reach embryos and pups, respectively. This passage modified the chemical element composition of foetus, and spleen and liver of mothers and their offspring. We showed that perinatal exposure to TiO early in life alters the gut microbiota composition, increases the intestinal epithelial permeability and enhances the colonic cytokines and myosin light chain kinase expression. Moreover, perinatal exposure to TiO also modifies the abilities of intestinal stem cells to survive, grow and generate a functional epithelium. Maternal TiO exposure increases the susceptibility of offspring mice to develop severe DSS-induced colitis later in life. Finally, transfer of TiO-induced microbiota dysbiosis to pregnant germ-free mice affects the homeostasis of the intestinal mucosal barrier early in life and confers an increased susceptibility to develop colitis in adult offspring.
CONCLUSIONS
Our findings indicate that foodborne TiO consumption during the perinatal period has negative long-lasting consequences on the development of the intestinal mucosal barrier toward higher colitis susceptibility. This demonstrates to which extent environmental factors influence the microbial-host interplay and impact the long-term mucosal homeostasis.
Topics: Pregnancy; Female; Animals; Mice; Dysbiosis; Lactation; Colitis; Inflammatory Bowel Diseases; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37996842
DOI: 10.1186/s12989-023-00555-5