Biology subjects

Parris, A. B.

Publications and source records attributed to Parris, A. B..

6 recordsLinked to original sources

bioRxiv2026

In Utero Alcohol Exposure Reprograms Mammary Gland Development and Stem/Progenitor Cell Activity in a Non-Tumorigenic Mouse Model

In utero alcohol exposure (IUE) can alter mammary development and increase mammary tumor susceptibility in experimental models. However, most previous studies have relied on carcinogen-induced or genetically tumor-prone models, leaving it unresolved whether prenatal alcohol exposure produces mammary developmental and molecular changes before the introduction of an oncogenic challenge. Here, we addressed this question using non-tumorigenic C57BL/6 mice. Pregnant dams received a Lieber-DeCarli liquid diet containing 1.7% (v/v) ethanol or an isocaloric control diet from gestational day 11 to 19, and mammary glands from female offspring were examined during puberty (postnatal day 40, PND40) and young adulthood (PND70). At PND40, IUE enhanced mammary ductal morphogenesis, increased terminal end bud numbers, and elevated epithelial proliferation. These developmental alterations persisted at PND70, with increased lateral branching and proliferative activity. IUE also altered mammary epithelial composition, expanding the basal/myoepithelial compartment and the CD24highCD49fhigh mammary repopulating unit/stem cell-enriched population. Mammary epithelial cells from IUE-exposed offspring exhibited increased colony-forming cells (CFCs), mammosphere formation, and 3D Matrigel growth, indicating enhanced stem/progenitor-associated activity. At the molecular level, IUE increased ER; expression and phosphorylation together with Cyclin D1, c-Myc, E2F1, and Bcl-2, and enhanced AKT, ERK, and STAT3 phosphorylation, IL-6 expression, and SOX2 at PND40. Importantly, major components of this signaling phenotype remained altered at PND70, including ER;-associated signaling, AKT/ERK activation, and IL-6/STAT3 signaling, whereas the pubertal increase in SOX2 was not sustained. Together, these findings demonstrate that prenatal alcohol exposure induces profound and persistent histomorphological, cellular, and signaling alterations in the mammary gland in the absence of a carcinogenic challenge or genetically introduced oncogenic driver. These results identify intrinsic developmental reprogramming of normal mammary tissue as a potential basis through which prenatal alcohol exposure may modify subsequent responses to tumor-promoting or other environmental challenges.

developmental biology↗

bioRxiv2026

Transcriptomic Analysis of the Newborn Mammary Gland Identifies Prenatal Ethanol-Induced Remodeling of Insulin Signaling and Enhanced Proliferative Programming

Prenatal alcohol exposure (PAE) can produce persistent alterations in mammary development and increase susceptibility to mammary tumorigenesis, but the early molecular events underlying these effects remain poorly understood. Here, we examined whether PAE alters the molecular program of the mammary gland at birth. Pregnant MMTV-ErbB2 mice received control or ethanol-containing liquid diets during gestation, and mammary tissues were collected from newborn female offspring. RNA sequencing revealed exposure-level-dependent transcriptional reprogramming, with substantially broader alterations following moderate compared with lower ethanol exposure. Pathway analyses identified prominent changes in metabolic and growth-regulatory networks, including insulin signaling, with coordinated alterations in components of the insulin/IGF-IRS-PI3K/AKT pathway. Biochemical analyses further demonstrated exposure-dependent changes in IGFBP expression and IRS1 abundance and phosphorylation, supporting remodeling of insulin/IGF-associated signaling. Transcriptomic analyses also revealed enrichment of RNA metabolic and translational processes and, particularly following moderate exposure, enhanced DNA-replication, cell-cycle, and mitotic programs. These molecular signatures were accompanied by increased proliferative features in newborn mammary tissue. Together, these findings demonstrate that PAE establishes substantial molecular reprogramming of the mammary gland by birth and identify altered insulin/metabolic signaling and proliferative programming as prominent features of this early developmental response.

developmental biology↗

bioRxiv2026

Chronic Alcohol Exposure Induces Persistent DNA Damage Response Signaling and Sensitizes Breast Epithelial Cells to PARP Inhibition

Chronic alcohol consumption is associated with increased breast cancer risk; however, the long-term effects of alcohol exposure on DNA damage response (DDR) signaling and therapeutic vulnerability in breast epithelial cells remain incompletely understood. In the present study, we established a chronic alcohol exposure model using immortalized human breast epithelial MCF-10A cells to investigate persistent alterations in DNA damage signaling and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. MCF-10A cells that chronically exposed to 0.2% alcohol for 20 weeks and then withdrew alcohol treatment for 4 weeks still retained elevated {gamma}H2AX levels and sustained activation of ATM/ATR-associated DDR pathways. Chronic alcohol-exposed cells also exhibited increased sensitivity to the PARP inhibitors olaparib and veliparib, as demonstrated by reduced cell viability, decreased clonogenic survival, and enhanced apoptosis. Mechanistically, olaparib induced greater G2/M checkpoint activation and replication-associated DNA damage in chronic alcohol-exposed cells compared with control cells. In addition, chronic alcohol exposure increased PARP expression and enhanced activation of DDR signaling following PARP inhibition. These findings demonstrate that chronic alcohol exposure induces persistent DNA repair stress and sensitizes breast epithelial cells to PARP inhibition. Our study suggests that chronic alcohol-associated genomic stress may create potential vulnerability to PARP inhibition.

cell biology↗

bioRxiv2026

Alcohol Promotes ER+ Breast Cancer Cell Proliferation and Invasion Through the Upregulation of Neuregulin 1-Mediated ER-ErbB3 Crosstalk

Alcohol consumption is an established risk factor for breast cancer, with a particularly strong association with estrogen receptor-positive (ER+) disease. Although the estrogenic activity of alcohol is well recognized, how alcohol-induced ER signaling is coupled to growth factor receptor pathways that promote tumor cell growth and progression remains incompletely understood. Here, we identify neuregulin-1 (NRG1) as a functional mediator, linking alcohol-induced ER activity to ErbB3 receptor tyrosine kinase signaling in ER+ breast cancer cells. Under estrogen-depleted conditions, alcohol induced proliferation, clonogenic growth, and S-phase progression in MCF-7 and T47D cells. Alcohol concurrently increased ER phosphorylation and transcriptional activity, including enhanced ER occupancy at the endogenous TFF1/pS2 regulatory region, and activated ErbB3 and downstream Akt, ERK, and p38 signaling. Notably, alcohol induced NRG1 expression in both cell lines. Pharmacological inhibition of ER signaling with ICI 182,780 (fulvestrant) substantially attenuated NRG1 induction, ErbB3/RTK activation, and alcohol-promoted growth, indicating that NRG1 induction and engagement of RTK signaling are strongly dependent on functional ER signaling. Conversely, shRNA-mediated NRG1 depletion suppressed alcohol-induced proliferation, clonogenic growth, and cell-cycle progression and markedly reduced alcohol-induced migratory and invasive phenotypes. NRG1 depletion also attenuated ErbB3/Akt/ERK signaling while reducing ER activation and ERE-dependent transcription, demonstrating a functional contribution of NRG1 to both arms of the signaling response. Together, these findings support a reciprocal ER-NRG1-ErbB3 signaling circuit in which alcohol-induced ER activity promotes NRG1 expression, while NRG1-dependent ErbB3 signaling reinforces ER activity and tumor-promoting phenotypes. Our study identifies NRG1 as a previously unrecognized molecular link between the estrogenic activity of alcohol and growth factor receptor signaling and provides a mechanistic framework for understanding alcohol-associated promotion of ER+ breast cancer.

cell biology↗

bioRxiv2026

Risk-Window Palbociclib Exposure Delays ErbB2-Driven Mammary Tumorigenesis and Suppresses Mammary Epithelial Cell Stemness

ErbB2 overexpression occurs in 15-20% of invasive breast cancer (BC) and inactivation of Cyclin D1-CDK4/6 axis reduce mammary stem/progenitor cells in ErbB2-driven tumorigenesis. Here, we explored the preventive role of short-term palbociclib intervention in MMTV-ErbB2 mice. Palbociclib significantly inhibited the proliferation and stemness of ErbB2-overexpressed BC cells in vitro and in vivo. Furthermore, short-term palbociclib exposure during the early premalignant risk window significantly delayed mammary tumor development and reduced tumor multiplicity, accompanied by the suppression of epithelial proliferation and ductal/alveolar morphogenesis in premalignant tissues, as well as prolonged tumor-free survival compared with controls. Importantly, palbociclib reduced the luminal epithelial (CD24high/CD49flow), mammary reconstitution unit-enriched (CD24high/CD49fhigh) subpopulations, and luminal progenitor/TIC-enriched (CD61high/CD49fmid) subpopulations. These changes were accompanied by diminished mammary epithelial cell stemness functions, including colony-forming, mammosphere-forming, and 3D growth activities of mammary epithelial cells. Mechanistically, palbociclib-treated tissues showed inhibition of the Cyclin D1-CDK4/6-RB-E2F axis and coordinated attenuation of ER-, ErbB2- and Wnt/{beta}-catenin-associated signaling. Together, we demonstrate that short-term CDK4/6 inhibition during a premalignant risk window produces a sustained delay in ErbB2-driven mammary tumorigenesis, associated with remodeling of the mammary epithelial hierarchy and suppression of proliferative and stem/progenitor-associated activity, suggesting CDK4/6 inhibition as a strategy for ErbB2-positive BC prevention.

cancer biology↗

bioRxiv2025

ALDH2 Deficiency Drives Proliferative Mammary Morphogenesis and Epithelial Cell Stemness via Oxidative Stress and Estrogen Receptor Activation

Alcohol consumption has been linked to breast cancer, partly due to the accumulation of toxic aldehydes like acetaldehyde, a carcinogenic byproduct of ethanol metabolism. ALDH2, a key mitochondrial enzyme, detoxifies acetaldehyde and other harmful aldehydes that drive oxidative stress, DNA damage, and hormonal dysregulation, key factors in carcinogenesis. Despite the possible link between alcohol consumption and breast cancer risk, little is known about how ALDH2 deficiency itself, independent of alcohol exposure, affects mammary gland biology and cancer susceptibility. Genetic variants leading to ALDH2 deficiency are highly prevalent in East Asian populations, where individuals carrying inactive ALDH2 alleles experience impaired aldehyde detoxification. While these individuals are at increased risk for alcohol-related cancers, the impact of ALDH2 deficiency on mammary gland development and homeostasis in the absence of alcohol exposure remains unexplored. To address this, we utilized a C57BL/6-based ALDH2 knockout (Aldh2-/-) mouse model to investigate its effects on mammary proliferation and development. Our findings revealed that Aldh2-/- mice exhibited hyperproliferative mammary glands, characterized by increased epithelial cell density, ductal expansion, and elevated Ki67+ cells. Flow cytometry analysis demonstrated a rise in luminal and basal epithelial subpopulations, alongside enhanced mammary epithelial stemness, as evidenced by increased mammosphere formation and colony-forming efficiency. At the molecular level, ALDH2 deficiency activated oxidative stress pathways, marked by elevated 8-OHdG, p38 MAPK, NF-{kappa}B, and Nrf2 signaling, alongside DNA damage responses involving p53 and H2A.X. Importantly, we also identified a previously unrecognized upregulation of RANKL in Aldh2-/- mammary glands, implicating the RANK/RANKL axis as a critical mediator linking aldehyde stress to NF-{kappa}B/p38 MAPK activation and enhanced mammary stemness. Furthermore, hormonal dysregulation was observed, with a significant increase in ER and PR expression and phosphorylation. Dysregulated ER signaling was further linked to enhanced erbB3 activation and downstream signaling, including the cyclin D1-pRb-E2F1 axis. Our results suggest that the accumulation of endogenous aldehydes, independent of alcohol exposure, profoundly alters mammary morphogenesis, epithelial repopulation, and stemness. Mechanistically, this occurs through oxidative stress activation and DNA damage pathways, leading to metabolic changes and upregulation of estrogen receptor and receptor tyrosine kinase signaling. This study highlights for the first time the potential role of ALDH2 deficiency in increasing mammary tissue susceptibility to oncogenic factors and breast cancer risk.

cancer biology↗