LPA receptor activity is basal specific and coincident with early pregnancy and involution during mammary gland postnatal development

Abstract

During pregnancy, luminal and basal epithelial cells of the adult mammary gland proliferate and differentiate resulting in remodeling of the adult gland. While pathways that control this process have been characterized in the gland as a whole, the contribution of specific cell subtypes, in particular the basal compartment, remains largely unknown. Basal cells provide structural and contractile support, however they also orchestrate the communication between the stroma and the luminal compartment at all developmental stages. Using RNA-seq, we show that basal cells are extraordinarily transcriptionally dynamic throughout pregnancy when compared to luminal cells. We identified gene expression changes that define specific basal functions acquired during development that led to the identification of novel markers. Enrichment analysis of gene sets from 24 mouse models for breast cancer pinpoint to a potential new function for insulin-like growth factor 1 (Igf1r) in the basal epithelium during lactogenesis. We establish that β-catenin signaling is activated in basal cells during early pregnancy, and demonstrate that this activity is mediated by lysophosphatidic acid receptor 3 (Lpar3). These findings identify novel pathways active during functional maturation of the adult mammary gland.

Development and validation of a targeted next generation DNA sequencing panel outperforming whole exome sequencing for the identification of clinically relevant genetic variants

“…RNA-Seq: All statistical methods, and data analysis were conducted using the R statistical software [ 28 ] as we previously described [ 29 ].…”

Intracellular Calcium links Milk Stasis to Lysosome Dependent Cell Death during Mammary Gland Involution

“…We found that milk stasis and loss of PMCA2 expression both upregulate TFEB expression and nuclear localization in vivo . This was associated with an increase in TFEB-regulated genes in previously published RNAseq data from involuting mouse mammary glands 44 . We also demonstrated that increased intracellular Ca 2+ increases TFEB expression and nuclear localization in mammary epithelial cells in vitro and this was also associated with an upregulation of TFEB-regulated genes based on RNAseq data.…”

“…5D, Fig.2). We also detected changes in gene expression consistent with activation of TFEB when we interrogated a RNAseq database which included mouse mammary glands harvested at day 10 of lactation and at day 2 of involution 44 . KEGG-identified gene set enrichment analysis demonstrated an increase in the expression of genes associated with lysosomes and autophagy at day 2 of involution as compared to lactation, both of which are regulated by TFEB (Fig.…”

Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities

“…However, multiple additional pathways influence MG development and function that are not necessarily captured by standard endocrine-sensitive endpoints (e.g., vaginal opening, estrous cyclicity, serum hormones, reproductive organ weights). For example, multiple stages of MG development are influenced by the aryl hydrocarbon receptor [252], progesterone [2,253], prolactin [254][255][256], insulin-like growth factors [253,255,257,258], transforming growth factor-α [259], and placental lactogens [260]. While some of these factors are also involved in other aspects of reproductive development [261][262][263][264][265] and may be detected in other typically measured endpoints, the interplay of these mechanisms and magnitude of effects likely differ between tissues.…”