Form and Function: how Estrogen and Progesterone Regulate the Mammary Epithelial Hierarchy

Arendt, Lisa M.; Kuperwasser, Charlotte

doi:10.1007/s10911-015-9337-0

Cited by 102 publications

(100 citation statements)

References 175 publications

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“…Prolactin is perhaps best known for its role in lactation [32]; however, it is also responsible for activating several other pathways such as the JAK-STAT pathway, including STAT3 [33, 34]. The function of STAT3 is well established in pregnancy, including involvement with embryonic implantation [35, 36], angiogenesis [37], and parturition [38, 39].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of circulating miRNAs during late pregnancy in the mare

et al. 2017

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MicroRNAs (miRNAs) are small, non-coding RNAs which are produced throughout the body. Individual tissues tend to have a specific expression profile and excrete many of these miRNAs into circulation. These circulating miRNAs may be diagnostically valuable biomarkers for assessing the presence of disease while minimizing invasive testing. In women, numerous circulating miRNAs have been identified which change significantly during pregnancy-related complications (e.g. chorioamnionitis, eclampsia, recurrent pregnancy loss); however, no prior work has been done in this area in the horse. To identify pregnancy-specific miRNAs, we collected serial whole blood samples in pregnant mares at 8, 9, 10 m of gestation and post-partum, as well as from non-pregnant (diestrous) mares. In total, we evaluated a panel of 178 miRNAs using qPCR, eventually identifying five miRNAs of interest. One miRNA (miR-374b) was differentially regulated through late gestation and four miRNAs (miR-454, miR-133b, miR-486-5p and miR-204b) were differentially regulated between the pregnant and non-pregnant samples. We were able to identify putative targets for the differentially regulated miRNAs using two separate target prediction programs, miRDB and Ingenuity Pathway Analysis. The targets for the miRNAs differentially regulated during pregnancy were predicted to be involved in signaling pathways such as the STAT3 pathway and PI3/AKT signaling pathway, as well as more endocrine-based pathways, including the GnRH, prolactin and insulin signaling pathways. In summary, this study provides novel information about the changes occurring in circulating miRNAs during normal pregnancy, as well as attempting to predict the biological effects induced by these miRNAs.

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Section: Discussionmentioning

confidence: 99%

Evaluation of circulating miRNAs during late pregnancy in the mare

et al. 2017

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“…Within the mammary gland, signaling by estrogen receptor α (ER-α) plays an essential role not only during glandular development and differentiation, but also during the initiation and progression of luminal breast cancers [6–8] . Indeed, the oncogenic activities of dysregulated ER-α signaling underlie the clinical success of anti-estrogen drugs ( e.g., tamoxifen) as first-line therapies to treat ER-positive breast cancers.…”

Section: Introductionmentioning

confidence: 99%

TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen resistance in breast cancer cells

Tian

Schiemann

2017

JCMT

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Aim Estrogen receptor-α (ER-α) activation drives the progression of luminal breast cancers. Signaling by transforming growth factor-β (TGF-β) typically opposes the actions of ER-α; it also induces epithelial-mesenchymal transition (EMT) programs that promote breast cancer dissemination, stemness, and chemoresistance. The impact of EMT programs on nongenomic ER-α signaling remains unknown and was studied herein. Methods MCF-7 and BT474 cells were stimulated with TGF-β to induce EMT programs, at which point ER-α expression, localization, and nongenomic interactions with receptor tyrosine kinases and MAP kinases (MAPKs) were determined. Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated. Results TGF-β stimulated MCF-7 and BT474 cells to acquire EMT phenotypes, which enhanced cytoplasmic accumulation of ER-α without altering its expression. Post-EMT cells exhibited (i) elevated expression of EGFR and IGF1R, which together with Src formed cytoplasmic complexes with ER-α; (ii) enhanced coupling of EGF, IGF-1 and estrogen to the activation of MAPKs; and (iii) reduced sensitivity to tamoxifen, an event reversed by administration of small molecule inhibitors against the receptors for TGF-β, EGF, and IGF-1, as well as those against MAPKs. Conclusion EMT stimulated by TGF-β promotes anti-estrogen resistance by activating EGFR-, IGF1R-, and MAPK-dependent nongenomic ER-α signaling.

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“…Estrogen signaling plays a central role in the normal development of the mammary gland, and the promotion of breast cancer (1, 2). Estrogen receptors (ERs) are ligand-regulated transcription factors consisting of subtypes α and β (3).…”

Section: Introductionmentioning

confidence: 99%

Effects of Pubertal Exposure to Dietary Soy on Estrogen Receptor Activity in the Breast of Cynomolgus Macaques

Dewi

Wood

Willson

et al. 2016

Cancer Prevention Research

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Endogenous estrogens influence mammary gland development during puberty and breast cancer risk during adulthood. Early-life exposure to dietary or environmental estrogens may alter estrogen-mediated processes. Soy foods contain phytoestrogenic isoflavones (IFs), which have mixed estrogen agonist/antagonist properties. Here, we evaluated mammary gland responses over time in pubertal female cynomolgus macaques fed diets containing either casein/lactalbumin (n=12) or soy protein containing a human-equivalent dose of 120 mg IF/day (n=17) for ~4.5 years spanning menarche. We assessed estrogen receptor (ER) expression and activity, promoter methylation of ERs and their downstream targets, and markers of estrogen metabolism. Expression of ERα and classical ERα response genes (TFF1, PGR and GREB1) decreased with maturity, independent of diet. A significant inverse correlation was observed between TFF1 mRNA and methylation of CpG sites within the TFF1 promoter. Soy effects included lower ERβ expression before menarche and lower mRNA for ERα and GREB1 after menarche. Expression of GATA-3, an epithelial differentiation marker that regulates ERα-mediated transcription, was elevated before menarche and decreased after menarche in soy-fed animals. Soy did not significantly alter expression of other ER activity markers, estrogen-metabolizing enzymes, or promoter methylation for ERs or ER-regulated genes. Our results demonstrate greater ER expression and activity during the pubertal transition, supporting the idea that this life stage is a critical window for phenotypic modulation by estrogenic compounds. Pubertal soy exposure decreases mammary ERα expression after menarche and exerts subtle effects on receptor activity and mammary gland differentiation.

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Form and Function: how Estrogen and Progesterone Regulate the Mammary Epithelial Hierarchy

Cited by 102 publications

References 175 publications

Evaluation of circulating miRNAs during late pregnancy in the mare

Evaluation of circulating miRNAs during late pregnancy in the mare

TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen resistance in breast cancer cells

Effects of Pubertal Exposure to Dietary Soy on Estrogen Receptor Activity in the Breast of Cynomolgus Macaques

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