Journal of Mammary Gland Biology and Neoplasia最新文献

Breast cancer is one of the most common malignancies worldwide. Circular RNAs (CircRNAs) were revealed to be implicated in the development of breast cancer. In this research, we aimed to investigate the role and underlying mechanism of circ_0008500 in the development and radiosensitivity of breast cancer. Using real-time quantitative PCR (RT-qPCR) and western blot, we found that hsa_circ_0008500 (circ_0008500) and profilin 2 (PFN2) were increased, while microRNA-758-3p (miR-758-3p) was decreased in breast cancer tissues and cells. Cell viability, the number of colonies, proliferation and apoptosis were detected using CCK-8, colony formation, EdU assays and flow cytometry, respectively. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were devoted to test the interaction between miR-758-3p and circ_0008500 or PFN2. The results showed that circ_0008500 knockdown inhibited cell growth, and facilitated cell apoptosis and radiosensitivity in breast cancer cells in vitro. Moreover, circ_0008500 regulated PFN2 expression by sponging miR-758-3p. Functionally, circ_0008500 knockdown regulated cell behaviors and radiosensitivity by targeting miR-758-3p to downregulate PFN2 expression in vitro. Additionally, in vivo tumor formation assay and immunohistochemistry (IHC) assay demonstrated that circ_0008500 knockdown enhanced the radiosensitivity and repressed tumor growth in vivo. In conclusion, circ_0008500 inhibition promoted the radiosensitivity and restrained the development of breast cancer by downregulating PFN2 expression via targeting miR-758-3p.

CCND1 is located on 11q13. Increased CCND1 copy number (CN) in breast cancer (BC) is associated with high histopathological grade, high proliferation, and Luminal B subtype. In this study of CCND1 in primary BCs and corresponding axillary lymph node metastases (LNM),we examine associations between CCND1 CN in primary BCs and proliferation status, molecular subtype, and prognosis. Furthermore, we studied associations between CCND1 CN and CNs of FGFR1 and ZNF703, both of which are located on 8p12. Fluorescence in situ hybridization probes for CCND1 and chromosome 11 centromere were used on tissue microarrays comprising 526 BCs and 123 LNM. We assessed associations between CCND1 CN and tumour characteristics using Pearson's χ² test, and estimated cumulative risks of death from BC and hazard ratios in analysis of prognosis. We found CCND1 CN ≥ 4 < 6 in 45 (8.6%) tumours, and ≥ 6 in 42 (8.0%). CCND1 CN (≥ 6) was seen in all molecular subtypes, most frequently in Luminal B (HER2^-) (20/126; 16%). Increased CCND1 CN was associated with high histopathological grade, high Ki-67, and high mitotic count, but not prognosis. CCND1 CN ≥ 6 was accompanied by CN increase of FGFR1 in 6/40 cases (15.0%) and ZNF703 in 5/38 cases (13.2%). Three cases showed CN increase of all three genes. High CCND1 CN was most frequent in Luminal B (HER2^-) tumours. Good correlation between CCND1 CNs in BCs and LNM was observed. Despite associations between high CCND1 CN and aggressive tumour characteristics, the prognostic impact of CCND1 CN remains unresolved.

Maternal health and diet can have important consequences for offspring nutrition and metabolic health. During lactation, signals are communicated from the mother to the infant through milk via macronutrients, hormones, and bioactive molecules. In this study we designed experiments to probe the mother-milk-infant triad in the condition of normal maternal health and upon exposure to high fat diet (HFD) with or without concurrent metformin exposure. We examined maternal characteristics, milk composition and offspring metabolic parameters on postnatal day 16, prior to offspring weaning. We found that lactational HFD increased maternal adipose tissue weight, mammary gland adipocyte size, and altered milk lipid composition causing a higher amount of omega-6 (n6) long chain fatty acids and lower omega-3 (n3). Offspring of HFD dams were heavier with more body fat during suckling. Metformin (Met) exposure decreased maternal blood glucose and several milk amino acids. Offspring of met dams were smaller during suckling. Gene expression in the lactating mammary glands was impacted to a greater extent by metformin than HFD, but both metformin and HFD altered genes related to muscle contraction, indicating that these genes may be more susceptible to lactational stressors. Our study demonstrates the impact of common maternal exposures during lactation on milk composition, mammary gland function and offspring growth with metformin having little capacity to rescue the offspring from the effects of a maternal HFD during lactation.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC), whereby if left untreated, approximately 12% of patients develop invasive disease. The current standard of care is surgical removal of the lesion, to prevent potential progression, and radiotherapy to reduce risk of recurrence. There is substantial overtreatment of DCIS patients, considering not all DCIS lesions progress to invasive disease. Hence, there is a critical imperative to better predict which DCIS lesions are destined for poor outcome and which are not, allowing for tailored treatment. Active surveillance is currently being trialed as an alternative management practice, but this approach relies on accurately identifying cases that are at low risk of progression to invasive disease. Two DCIS-specific genomic profiling assays that attempt to distinguish low and high-risk patients have emerged, but imperfections in risk stratification coupled with a high price tag warrant the continued search for more robust and accessible prognostic biomarkers. This search has largely turned researchers toward the tumor microenvironment. Recent evidence suggests that a spectrum of cell types within the DCIS microenvironment are genetically and phenotypically altered compared to normal tissue and play critical roles in disease progression. Uncovering the molecular mechanisms contributing to DCIS progression has provided optimism for the search for well-validated prognostic biomarkers that can accurately predict the risk for a patient developing IDC. The discovery of such markers would modernize DCIS management and allow tailored treatment plans. This review will summarize the current literature regarding DCIS diagnosis, treatment, and pathology.

Heat stress and mastitis adversely affect milk production in dairy ruminants. Although the udder temperature is elevated in both conditions, the influence of this local temperature rise on milk production and immune function of ruminant mammary glands remains unclear. To address this question, we heated the mammary glands of goats by covering one half of the udder with a disposable heating pad for 24 h, the other uncovered half served as a control. Sixteen Tokara goats (1-5 parity) and three Shiba goats (1-2 parity) at the mid-lactation stage were individually housed, fed 0.6 kg of hay cubes and 0.2 kg of barley per day, and had free access to water and trace-mineralized salt blocks. Milk samples were collected every 6 h for 24 h after covering (n = 16), and deep mammary gland tissue areas were collected after 24 h (n = 5). The concentrations of antimicrobial components [lactoferrin, β-defensin-1, cathelicidin-2, cathelicidin-7, and immunoglobulin A (IgA)] in milk were measured by the enzyme-linked immunosorbent assay (ELISA). The localization of IgA was examined by immunohistochemistry. The mRNA expression and protein concentrations of C-C motif chemokine ligand-28 (CCL-28) and interleukin (IL)-8 in the mammary gland tissue were measured using quantitative polymerase chain reaction and ELISA, respectively. The somatic cell count in milk was significantly higher in the local heat-treatment group than in the control group after 12 h of treatment. The treatment group had significantly higher concentrations of cathelicidin-2 and IgA than the control group after 24 h of treatment. In addition, the number of IgA-positive cells in the mammary stromal region and the concentration of CCL-28 in the mammary glands were increased by local heat treatment. In conclusion, a local rise in udder temperature enhanced the innate immune function in mammary glands by increasing antimicrobial components.

Breast cancer (BC) is the leading cause of cancer-related death in women in the world. Since tumor cells employ autophagy as a survival pathway, it has been proposed that autophagy inhibition could be beneficial for cancer treatment. There are several onging clinical trials where autophagy is being inhibited (using chloroquine, CQ or hydroxychloroquine, HCQ) along with chemotherapy with promising results. However, there is also in vitro evidence in which autophagy inhibition can induce epithelial to mesenchymal transition (EMT) in cancer cells, indicating that, at least in some cases, this strategy could be detrimental for cancer patients. In this study, we found that the genetic inhibition of autophagy primed cells for EMT by inducing a decrease in E-cadherin protein levels, while CQ treatment decreased E-cadherin levels, induced morphological changes related to EMT, increased EMT-related transcription factor (EMT-TF) expression and migration in estrogen receptor positive (ER +) BC cell lines. Importantly, CQ treatment increased intracellular reactive oxygen species (ROS) which induced the secretion of macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine related to malignancy. Both ROS production and MIF secretion were responsible for the mesenchymal morphology and increased migratory capacity induced by CQ. Our results indicate that CQ treatment increased malignancy by inducing ROS production, MIF secretion and EMT and suggest that autophagy inhibition in ER + BC patients might have detrimental effects. Our data indicates that a careful selection of patients should be performed in order to determine who will benefit the most from autophagy inhibition with available pharmacological agents for the treatment of breast cancer.

Stem-cell containing mammary basal epithelial cells exist in a quasi-mesenchymal transcriptional state characterized by simultaneous expression of typical epithelial genes and typical mesenchymal genes. Whether robust maintenance of such a transcriptional state is required for adult basal stem cells to fuel self-renewal and regeneration remains unclear. In this work, we utilized SMA-CreER to direct efficient basal cell-specific deletion of Ovol2, which encodes a transcription factor that inhibits epithelial-to-mesenchymal transition (EMT), in adult mammary gland. We identified a basal cell-intrinsic role of Ovol2 in promoting epithelial, and suppressing mesenchymal, molecular traits. Interestingly, Ovol2-deficient basal cells display minimal perturbations in their ability to support tissue homeostasis, colony formation, and transplant outgrowth. These findings underscore the ability of adult mammary basal cells to tolerate molecular perturbations associated with altered epithelia-mesenchymal plasticity without drastically compromising their self-renewal potential.

Ductal carcinoma in situ (DCIS) of the breast is able to induce stromal changes, which likely reflect the crosstalk between DCIS and its microenvironment. These changes harbor prognostic information, although the interobserver variability of scoring stromal changes is moderate. A more robust evaluation of the DCIS-associated stroma is therefore needed. The aim of this study was to characterize P4HA2 expression, which is involved in collagen biosynthesis, in DCIS and to assess whether P4HA2 expression enables a more robust evaluation of the DCIS-associated stroma compared to histomorphology. This study included 410 patients with DCIS. Stromal changes were scored on hematoxylin/eosin-stained whole slides. P4HA2 expression in DCIS-associated stroma was assessed by whole slide immunohistochemistry. One hundred DCIS lesions were evaluated by seven pathologists to study the interobserver variability in the assessment of stromal changes and stromal P4HA2 expression. High P4HA2 expression in stromal fibroblasts was present in 14.1% of the patients. High P4HA2 expression was associated with the presence of periductal stromal changes (P = 0.004). The interobserver variability was similar for the assessment of stromal changes and the percentage of P4HA2-positive fibroblasts. Although we demonstrated a significant association between high P4HA2 expression in fibroblasts and the morphological presence of stromal changes, it seems unlikely that P4HA2 expression can be used as an alternative for the histopathological evaluation of the DCIS-associated stroma.