Biology subjects

Marino, N.

Publications and source records attributed to Marino, N..

5 recordsLinked to original sources

bioRxiv2024

Systematic dissection of epigenetic age acceleration in normal breast tissue reveals its link to estrogen signaling and cancer risk

Breast aging encompasses intricate molecular and cellular changes that elevate cancer risk. Our study profiled DNA methylation and gene expression of 181 normal breast samples and systematically evaluated eight epigenetic clocks. We found that clocks trained using breast tissues demonstrate improved age prediction in normal breast tissue, and bias universally exists in epigenetic clocks, necessitating a proper definition of age acceleration. Cell composition analysis revealed significant age-related alterations and highlighted its distinct associations with age acceleration, including increased luminal epithelial and myoepithelial cells and reduced adipocytes and immune cells, connecting age acceleration to carcinogenesis from a cell compositional perspective. Additionally, CpG sites associated with age acceleration were enriched for estrogen receptor binding sites, providing a mechanistic link between estrogen exposure, accelerated aging, and cancer. These findings highlight the importance of cellular heterogeneity in epigenetic age estimates and the potential of age acceleration to guide for risk stratification and prevention strategies.

bioinformatics↗

bioRxiv2021

Reciprocal interactions between the gut microbiome and mammary tissue mast cells promote metastatic dissemination of HR+ breast tumors

Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, prior to breast tumor initiation, enhances early dissemination of hormone-receptor positive (HR+) mammary tumor cells. Here, we sought to define mammary tissue mediators of dysbiosis-induced tumor dissemination. We found that commensal dysbiosis increased both the frequency and profibrogenicity of mast cells in the mammary tissue, a phenotypic change that persisted after tumor implantation. Fibroblast activation and tissue remodeling associate with enhanced breast tumor metastasis. We employed pharmacological and adoptive transfer approaches to demonstrate that mammary tissue mast cells from dysbiotic animals enhances dissemination of HR+ tumor cells. Collagen levels in mammary tissues from HR+ breast cancer patients correlated with mast cell abundance, suggesting clinical relevance of mast cell-mediated fibroblast activation. Together, these data demonstrate that a gut-mast cell axis exists that induces fibroblast activation and orchestrates early dissemination of HR+ breast tumors. SignificanceOur study defines the mechanism by which an inflammatory gut microbiome facilitates HR+ breast tumor cell dissemination. We establish that gut commensal dysbiosis triggers mammary tissue mast cells to facilitate early metastatic dissemination. These findings highlight a novel gut microbiome-innate immune cell axis involved in negative breast cancer outcomes.

cancer biology↗

bioRxiv2021

Aberrant epigenetic and transcriptional events associated with breast cancer risk

BackgroundGenome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N=146, median age=39 years) were processed for both methylome (MethylCap) and transcriptome (Illuminas HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation. ResultsTranscriptomic analysis identified 69 differentially expressed genes between women at either high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR<0.05 and fold change[≥]2. The majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR<0.01) and primary epithelial cells (p<0.05) from high-risk breasts. Moreover, 1698 DNA methylation aberrations were identified in high-risk breast tissues (FDR<0.05), partially overlapped with cancer-related signatures and correlated with transcriptional changes (p<0.05, r[≤]0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified. ConclusionsNormal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.

cancer biology↗

bioRxiv2019

Multiscale activity imaging in the mammary gland reveals how oxytocin enables lactation

The mammary epithelium is indispensable for the continued survival of more than 5000 mammalian species. For some, the volume of milk ejected in a single day exceeds their entire blood volume. Here, we unveil the spatiotemporal properties of physiological signals that orchestrate milk ejection. Using quantitative, multidimensional imaging of mammary cell ensembles, we reveal how stimulus evoked Ca2+ oscillations couple to contractions in basal epithelial cells. Moreover, we show that Ca2+-dependent contractions generate the requisite force to physically deform the innermost layer of luminal cells, compelling them to discharge the fluid that they produced and housed. Through the collective action of thousands of these biological positive displacement pumps, each linked to a contractile ductal network, milk is delivered into the mouth of the dependent neonate, seconds after the command. Significance StatementThe mammary gland is functional for only a brief period of a females lifetime--if at all. During this time, it operates not for the survival of the individual, but for the survival of her species. Here, we visualize the nature of alveolar contractions in the functionally-mature mammary gland, revealing how specialized epithelial cells, which possess the ability to behave like smooth muscle cells, undergo Ca2+-dependent contractions. We demonstrate that individual oscillators can be electrically coupled to achieve global synchrony, a phenomenon that has not yet been observed in the mammary gland. By imaging activity across scales, we provide a window into the organization, dynamics and role of epithelial Ca2+ oscillations in the organ principally responsible for sustaining neonatal life in mammals.

cell biology↗

bioRxiv2019

Mammary mechanobiology: PIEZO1 mechanically-activated ion channels in lactation and involution

A mothers ability to produce a nutritionally-complete neonatal food source has provided a powerful evolutionary advantage to mammals. Milk production by secretory mammary epithelial cells is adaptive, its release is exquisitely timed and its own glandular stagnation with the permanent cessation of suckling triggers the programmed cell death and tissue remodeling that enables female mammals to nurse successive progeny. Both chemical and mechanical signals control epithelial expansion, function and remodeling. Despite this duality of input, however, the nature and function of mechanical forces in the mammary gland remain unknown. Here, we characterize the mammary force landscape and the capacity of luminal and basal epithelial cells to experience and exert force. We explore the molecular instruments for force-sensing in the mammary gland and the physiological requirement for PIEZO1 in lactation and involution. Our study supports the existence of a multifaceted system of chemical and mechanical sensing in the mammary gland, and a protective redundancy that ensures continued lactational competence and offspring survival.

cell biology↗