Glande mammaire | EPFL Graph Search

Les glandes mammaires sont les glandes des mamelles des mammifères mâles et femelles. Elles ont la particularité de sécréter le lait servant à l'allaitement de la progéniture. Les glandes mammaires sont, embryologiquement, des modifiées ayant initialement pour fonction de protéger des infections les œufs de mammifères protothériens. Chez l'être humain thumb|Glande mammaire humaine1 : Cage thoracique 2 : Muscles pectoraux 3 : Lobules 4 : Surface du mamelon 5 : Aréole 6 : Conduit galactophore 7 : Tissu adipeux 8 : Peau. Chez l'être humain, l’homme aussi possède une glande mammaire mais elle n’est pas développée, chaque glande comprend 15 à 20 lobes séparés par du tissu adipeux, dont la quantité détermine le volume des seins. Ces lobes sont reliés au mamelon par les canaux mammaires, puis les canaux lactifères (ou galactophores). Le sein est soutenu dans sa partie supérieure par des bandes de tissu conjonctif appelées ligam

Hormonal regulation of Stat5 in the mammary gland - from signaling to morphogenesis

Sergio Klinke

The mammary gland development is regulated by steroid and peptide hormones and occurs mainly after birth, compared to the majority of the other organs in the body. The principal hormones responsible for the breast development are the estrogen, the progesterone, the growth hormone, the epidermal growth factor and the prolactin. The latter one is of specific interest since it is required for further development of the gland through pregnancy and lactation. During pregnancy and lactation, alveolar structures develop and differentiate into secretory cells. The signal transducer and activator of transcription 5 (Stat5) is known to be the main effector of prolactin signaling during pregnancy, inducing alveologenesis and differentiation of epithelial cells into secretory cells. I investigated if Stat5 has a role before pregnancy. Protein expression as well as mRNA expression analysis of glands from ovariectomized mice which were artificially stimulated with ovarian hormones (estrogen and progesterone) and control vehicle showed evidences that Stat5 expression can be stimulated by these two hormones. Contrary to the role established until now for stat5 in the mammary gland, I found by fluorescence visualization of Stat5-null epithelium as well as whole mount staining of the same glands that Stat5 is required even before pregnancy since null epithelium showed highly reduced growth already in 3 weeks-old virgin mice. This may indicate a new role for this protein in cell proliferation or survival in early stages of mouse mammary development. Furthermore, transplantation experiment of Stat5-null epithelium into wild-type recipient mice showed that pregnancy state was not able to rescue the normal phenotype. This may be due to complete loss of these cells which happened during the 5 weeks left for the transplanted epithelium to expand the cleared fat pad. This discovery opens a new debate on Stat5 role in the mammary gland development.

2008

Probing the differential adhesion hypothesis in the mammary gland using different bioengineered cell culture substrata

Léa Chanson

During tissue development, cells are able to form different layers and to self organize. At the moment, there are two principal hypotheses that try to explain cell sorting. The so called differential adhesion hypothesis (DAH) posits that cells organize according to the level of expression of cell-cell adhesion proteins so as to reduce free-energy in the system. The second hypothesis explains the formation of different germ layers according to cortical tension among cells of distinct phenotypes. For this work, we wanted to study cell sorting in the mammary glands, which are bilayered branching structures composed of outer myoepithelial (MEP) and inner luminal epithelial cells (LEP). Both sorting hypotheses were tested using bioengineered cell culture substrata. Using arrays of micro-wells that were cast in polydimethylsiloxane (PDMS) coupled with quantitative image analysis, we observed that cell sorting occurred over time between LEP and MEP that were isolated by fluorescence-activated cell sorting from primary human mammary epithelial cells. Inhibitors of specific cadherins were able to prevent cell sorting in accordance with the DAH. However, chemical inhibitors of cytoskeletal proteins, which effectively prevented the cells from modulating their innate elasticity, also prevented cell sorting suggesting cortical tension also plays an important role. Thus, our data suggests a third hypothesis, which is essentially a unification of the original two, such that differences in cortical tension are essentially lineage-specific and are governed wholly or in-part by cell-cell adhesion molecules. Experimental resolution of this hypothesis is being actively pursued

2009

Mechanisms underlying cell-fate determination in the mammary gland development

Duje Buric

Notch signaling pathway is an important developmental pathway and has been implicated in both mammary gland development and tumorigenesis. Several studies investigating Notch signaling in mouse mammary gland implied that Notch signaling is an important factor in the determination of the luminal cell type. Clinical studies on breast tumors as well as studies in transgenic mouse models overexpressing active Notch receptors suggested an oncogenic function of Notch in the mammary gland connecting it to the poor breast cancer prognosis. However the physiological role of Notch signaling and its downstream mechanisms remain unclear. Analysis of Transgenic-EGFP Notch reporter mouse mammary epithelium revealed that Notch signaling is active specifically in a subset of hormone receptor positive cells. More sensitive FACS analysis consistently shows EGFP expression in HR+ luminal cells and reveals a weaker signal in a subset of basal (CD24lo) cells. Additionally mRNA analysis revealed that Notch active luminal cells are expressing Wnt4 ligand. To unveil the role of the Notch signaling in the Wnt4 expressing HR+ cells, we conditionally deleted RBP-Jκ, Notch signaling mediator, in Wnt4 expressing subpopulation of hormone receptor positive cells via Wnt4Cre. Abrogation of RBP-Jκ resulted in loss of progesterone receptor expression in 90% of cells bearing the RBP-Jκ deletion while estrogen receptor expression remained intact, implicating RBP-Jκ in regulation of progesterone receptor expression. To test whether Notch signaling regulates PR expression in the entire HR+ population, we analyzed mammary epithelium in which RBP-Jκ has been conditionally deleted via MMTV-Cre in progenitor cells revealing the presence of a subpopulation of luminal hormone receptor positive cells that differentiate independently of Notch signaling. Time directed deletion of RBP-Jκ via intraductally injected Adeno-Cre virus into the adult mouse mammary ductal system through the nipple additionally confirmed that RBP-Jκ is required for progesterone receptor expression. Chromatin immunoprecipitation assay showed that RBP-Jκ binds two out of four putative RBPJκ binding sites in the progesterone receptor promoter. Inhibition of Notch signaling in vivo via intraductal injection of γ-secretase inhibitor, DAPT, resulted in reduced progesterone receptor expression strongly suggesting that Notch-related RBP-Jκ signaling is responsible for PR expression. In this project we are proposing that there are two different populations of HR+ cells: one defined as Wnt4 expressing subpopulation of HR+ cells in which PR expression is dependent of Notch signaling, and another one defined as Wnt4 non expressing subpopulation of HR+ cells which is independent of Notch signaling. Since Notch signaling is able to replace ER signaling and activate ER target genes in the endocrine therapy resistant cell lines, Wnt4 expressing population of HR+ luminal cells might play a crucial role in the acquiring of the resistance.

EPFL2015