Journal of Mammary Gland Biology and Neoplasia最新文献

Cellular plasticity in mammary epithelial cells enables dynamic cell state changes essential for normal development but can be hijacked by breast cancer cells to drive tumor progression and metastasis. However, the molecular factors that maintain cellular plasticity through the regulation of a hybrid cell state (epithelial/mesenchymal) are not fully defined. As LMO2 has been previously shown to regulate metastasis in breast cancer, here we determine the role of LMO2 in normal mammary epithelial cells. Using lineage tracing and knockout mouse models, we find that Lmo2 lineage-traced cells are present in the luminal and basal layer of the mammary gland but have limited proliferative potential. Lmo2 loss does not impact mammary gland development, but acute deletion decreases in vivo reconstitution. Moreover, LMO2 knockdown in mouse and human mammary epithelial cells (MECs) reduces organoid formation. We find that LMO2 regulates the epithelial cell state in MECs and LMO2 knockdown promotes mesenchymal differentiation. Transcriptional profiling of LMO2 knockdown cells reveals significant enrichment in the epithelial-mesenchymal transition (EMT) pathway and upregulation of MCAM, a mesenchymal marker and negative regulator of regenerative capacity in the mammary gland. Altogether, we show that LMO2 plays a role in maintaining cellular plasticity in MECs, adding insight into the normal differentiation programs hijacked by cancer cells to drive tumor progression.

The study of breast cancer is complicated by the heterogeneity inherent within the disease. Numerous models have been developed to study the initiation, progression, and treatment of breast cancer. These include carcinogen induced mouse models, genetically engineered mouse models, and patient derived xenografts. The relevance of these mouse models to humans must be precisely defined for appropriate understanding of disease mechanisms to derive intervening treatments. Sequencing projects such as The Cancer Genome Atlas Project (TCGA) and Catalogue Of Somatic Mutations In Cancer (COSMIC) were pivotal developments in understanding driving events in human cancers. These studies have revealed that in addition to activation of strong oncogenes, or loss of tumor suppressors, that secondary events are necessary for tumor development and progression. These techniques should also be applied to mouse models of human breast cancer. For all the available models studied and reviewed here, whole genome sequencing (WGS) in conjunction with gene expression analysis has revealed conserved events between human and mouse model systems. This identification of conserved, critical events driving breast cancer has led to novel targets based on breast cancer subtype, ultimately resulting in new therapeutic opportunities. The combination of sequencing and choice of the appropriate mouse model can provide a powerful tool in developing appropriate pre-clinical models of breast cancer.

Studies in breast cancer have demonstrated that apatinib exhibits both antiangiogenic and antitumor effects, while PD-L1 inhibitors have similarly shown meaningful clinical benefit. Building upon these observations, this study evaluated the potential synergistic antitumor effects of combining apatinib with a PD-L1 inhibitor and examined the mechanistic basis for their interaction in breast cancer. Notably, we found that this regimen could significantly suppress the proliferation, migration, and invasion of MCF-7 and MDA-MB-231 cells, and promote cell apoptosis. In addition, the levels of p-ERK, NF-κB, and Slug were markedly reduced in vitro. Collectively, these findings support the potential clinical utility of combining apatinib and PD-L1 inhibition, as evidenced by consistent in vitro and in vivo synergy.

Reproduction studies are important for the conservation of cetaceans (whales, dolphins, and porpoises) because they provide essential information for assessing populations and species dynamics, particularly in relation to the management of the diverse cetacean species in human care. A vast majority of literature on the female cetacean reproductive anatomy and physiology has focused on the ovaries, which can be used to infer reproductive history, or genital diseases and anomalies. However, literature regarding the morphology, physiology, and developmental pattern of cetacean mammary glands is scarce, despite their fundamental role in providing vital nutrients for the growth of offspring. This review describes current diagnostic tools applied in human and veterinary medicine to assess mammary glands and how marine mammal medicine could benefit from incorporating these tools into standard evaluation of the mammary glands in free-ranging and captive cetaceans. By evaluating the strengths and weaknesses of the current tools used to assess the mammary glands in humans and domestic animals -such as mammography, CT, MRI and ultrasonography- we frame a collection of diagnostic approaches that might be adapted to the particular challenges faced by marine mammal veterinarians, to enhance the evaluation of cetacean mammary gland morphology, physiology and development.

Fibroblast growth factor receptors (FGFRs) are critical mediators of cellular signaling involved in development, tissue repair, and metabolic homeostasis. Dysregulated FGFR signaling is also a common feature in multiple cancer types, including breast cancer. In breast cancer, aberrant FGFR signaling can occur by amplification, mutation, isoform switching, or gene fusion and has emerged as a driver of tumor progression, metastasis, and therapeutic resistance. Beyond its canonical roles in proliferation and survival, recent evidence highlights FGFRs as key regulators of cancer cell metabolism. This review summarizes current findings on how FGFR signaling reprograms metabolic pathways in breast cancer, specifically glycolytic and lipid metabolism. We explore the interplay between FGFR activity and metabolic enzymes, transcription factors, and nutrient-sensing pathways, emphasizing subtype-specific metabolic vulnerabilities. Furthermore, we discuss how FGFR-mediated metabolic plasticity contributes to tumor heterogeneity and resistance to targeted therapies. Understanding the metabolic functions of FGFR signaling offers new opportunities for therapeutic intervention and biomarker development in breast cancer.

Among breast cancer subtypes, basal-like breast cancer (BLBC) is a highly aggressive form characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor (HER2) expression and is associated with poor prognosis, leaving chemotherapy as the sole treatment option available. Loss-of-function mutations in BRCA1 are strongly associated with the development of BLBC. Patients with this subtype are more likely to have grade III tumors and larger average tumor sizes than those with other subtypes of breast cancer. It is not known whether BRCA1 loss of function affects all cell types equally within breast tissue or if it has a preferential malignant impact on specific cell types, leading to the progression of lineage-specific tumorigenesis in the breast epithelium of women carrying BRCA1 mutations. Lineage tracing experiments using genetically engineered mouse models have provided critical insights into how BRCA1 loss alters cellular hierarchy within the mammary gland. These studies have demonstrated that BRCA1-deficient luminal progenitors can aberrantly differentiate into basal-like cells, suggesting that BLBC may arise from a misregulated luminal compartment rather than pre-existing basal stem cells. Understanding the mechanisms underlying BRCA1-mediated lineage plasticity offers novel therapeutic avenues to target early-stage tumor initiation and progression in BRCA1-mutated breast cancer. This review perspective sheds light on the role of BRCA1 in lineage plasticity and highlights probable mechanisms by which BRCA1 could promote this lineage plasticity.

The neglect of research into women's health and female biology has had major impacts for the fields of mammary biology and cancer. A quarter of the way through the twenty-first century, we still lack basic knowledge regarding the formation and function of the organ that gives its name to all mammals, and which provides important health benefits for children and their breastfeeding parent through the creation and delivery of breast milk. In this review, we highlight key similarities and differences in mouse and human mammary glands, and discuss how both systems of investigation are important and necessary to fill outstanding knowledge gaps. We discuss important discoveries that have arisen through mouse models as well as methodological advances that have enabled more widespread investigations in human samples. Finally, we contend that the translatability of mammary gland research requires thoughtful design, careful evaluation and continued review, irrespective of the system of investigation.

Epithelial-mesenchymal transition (EMT) is a well-known phenomenon that has been implicated in diverse biological processes ranging from embryonal development to cancer invasion and metastasis. In epithelial-derived cancers which both invade and metastasize as epithelial clumps or clusters, EMT would have to be followed by MET (mesenchymal-epithelial transition) since both the initial cancer and the metastasis appear epithelial in nature. There is a rare subset of breast carcinomas, however, that exhibit biphasic epithelial and mesenchymal differentiation, so-called metaplastic carcinomas. Our initial studies were designed to examine whether EMT was indeed occurring in this unique subset of metaplastic breast carcinomas. Based on both RT-PCR and immunocytochemical studies, EMT was naturally occurring. Once this was confirmed, we wanted to investigate the effects of EMT beyond the immediate gene expression pattern that traditionally defined it. Although approximately 90% of metaplastic breast carcinomas are triple negative, 5-10% amplify and overexpress HER2. We then conducted both observational studies in these biphasic HER2 overexpressing metaplastic breast carcinomas and experimental studies with a HER2 overexpressing cell line, the HTB20, where TGFβ1 induced EMT. In the observational studies, HER2 gene amplification was equally present in both the epithelial and mesenchymal phases but both HER2 mRNA and protein levels were essentially silenced in the areas having undergone EMT. Similarly in the experimental studies where TGFβ1 induced EMT, HER2 gene amplification persisted but HER2 mRNA and protein levels were similarly silenced. These studies provide direct evidence that both naturally occurring and induced EMT results in epigenetically silencing of HER2 overexpression.