Metabolic Stress Adaptations Underlie Mammary Gland Morphogenesis and Breast Cancer Progression

Breast cancers display dynamic reprogrammed metabolic activities as cancers develop from premalignant lesions to primary tumors, and then metastasize. Numerous advances focus on how tumors develop pro-proliferative metabolic signaling that differs them from adjacent, non-transformed epithelial tissues. This leads to targetable oncogene-driven liabilities among breast cancer subtypes. Other advances demonstrate how microenvironments trigger stress-response at single-cell resolution. Microenvironmental heterogeneities give rise to cell regulatory states in cancer cell spheroids in three-dimensional cultures and at stratified terminal end buds during mammary gland morphogenesis, where stress and survival signaling juxtapose. The cell-state specificity in stress signaling networks recapture metabolic evolution during cancer progression. Understanding lineage-specific metabolic phenotypes in experimental models is useful for gaining a deeper understanding of subtype-selective breast cancer metabolism.

BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models

Elucidation of non-canonical protein functions can identify novel tissue homeostasis pathways. Herein, we describe a role for the Bcl-2 family member BAD in postnatal mammary gland morphogenesis. In Bad3SA knock-in mice, where BAD cannot undergo phosphorylation at 3 key serine residues, pubertal gland development is delayed due to aberrant tubulogenesis of the ductal epithelium. Proteomic and RPPA analyses identify that BAD regulates focal adhesions and the mRNA translation repressor, 4E-BP1. These results suggest that BAD modulates localized translation that drives focal adhesion maturation and cell motility. Consistent with this, cells within Bad3SA organoids contain unstable protrusions with decreased compartmentalized mRNA translation and focal adhesions, and exhibit reduced cell migration and tubulogenesis. Critically, protrusion stability is rescued by 4E-BP1 depletion. Together our results confirm an unexpected role of BAD in controlling localized translation and cell migration during mammary gland development.

Evaluation of key miRNAs during early pregnancy in Kazakh horse using RNA sequencing

Background miRNA has an important role in cell differentiation, biological development, and physiology. Milk production is an important quantitative trait in livestock and miRNA plays a role in the amount of milk produced. Methods The role of regulatory miRNAs involved in equine milk production is not fully understood. We constructed two miRNA libraries for Kazakh horse milk production from higher-producing (H group) and lower-producing (L group) individuals, and used RNA-Seq technology to identify the differentially expressed miRNAs between the two milk phenotypes of Kazakh horses. Results A total of 341 known and 333 novel miRNAs were detected from the H and L groups, respectively. Eighty-three differentially expressed miRNAs were identified between the H and L group s, of which 32 were known miRNAs (27 were up-regulated, five were down-regulated) and 51 were novel miRNAs (nine were up-regulated, 42 were down-regulated). A total of 2,415 genes were identified. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that these genes were annotated to mammary gland development, mammary gland morphogenesis, tissue development and PI3K-Akt signaling pathways, insulin signaling pathway and TGF-beta signaling pathway, among others. Five miRNAs (miR-199a-3p, miR143, miR145, miR221, miR486-5p) were identified as affecting horse milk production and these five miRNAs were validated using qRT-PCR. Conclusions We described a methodology for the transcriptome-wide profiling of miRNAs in milk, which may help the design of new intervention strategies to improve the milk yield of Kazakh horses.