Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression

Clarkson, Richard W. E.; Wayland, Matthew T.; Lee, Jennifer; Freeman, Tom C.; Watson, Christine J.

doi:10.1186/bcr754

Cited by 302 publications

(184 citation statements)

References 74 publications

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“…In this process, the remaining MFGs are also cleared from the gland (8). The involution process is regulated at the transcriptional level and is associated with the up-or down-regulation of a set of genes (26,27). In this report, we showed that the MFG-E8 gene was strongly expressed in the mammary gland during the lactation and involution periods.…”

Section: Discussionmentioning

confidence: 57%

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Hanayama

Nagata

2005

Proc. Natl. Acad. Sci. U.S.A.

120

118

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During the involution of mammary glands, epithelial cells undergo apoptosis and are cleared for the next cycle of lactation. The clearance of apoptotic epithelial cells is mediated by neighboring epithelial cells and by macrophages that migrate into the mammary glands. Here, we report that milk fat globule EGF factor 8 (MFG-E8), a secreted glycoprotein that binds to apoptotic cells by recognizing phosphatidylserine, was expressed by epithelial cells and macrophages in mammary glands and was involved in engulfment of apoptotic cells. A deficiency of MFG-E8 caused the accumulation of a large number of milk fat globules (MFGs) in the mammary ducts during involution, indicating that the excess MFGs were cleared by an MFG-E8-dependent mechanism. The MFG-E8 ؊/؊ mice developed mammary duct ectasia with periductal mastitis, and the redevelopment of the mammary gland for their second litter was impaired. These results demonstrate that MFG-E8-mediated phagocytosis of apoptotic epithelial cells and MFGs is important for efficient involution of mammary glands.exosomes ͉ mastitis ͉ phosphatidylserine M ammary glands are unique mammalian organs that are developed to nurse offspring. For each pregnancy, the glands undergo a cycle of development, lactation, and involution. In each cycle, mammalian epithelial cells proliferate, differentiate, and die. The involution of mammary glands is triggered when the suckling stimulus is lost, usually upon weaning, and milk accumulates in the glands. The involution takes Ϸ10 days in mice and can be divided into two phases (1-3). In the first phase, which is reversible and lasts 48 h after weaning, mammary epithelial cells lose their differentiated function. In the second phase, the basement membranes and extracellular matrix in the mammary glands are degraded by proteases, leading to destruction of the lobular-alveolar architecture of the mammary glands. As involution progresses, mammary epithelial cells are removed and adipocytes concomitantly reappear, and the lobular-alveolar structure is reorganized to approach that of virgin glands (4).During the involution process, epithelial cells undergo apoptosis and are shed into the lumen (5). At the initial stage of involution, these apoptotic cells are thought to be engulfed mainly by neighboring epithelial cells; in the later stage, they seem to be cleared by macrophages that migrate into the gland (3, 6). Milk fat globules (MFGs) are minute globules carrying fat that are secreted from the epithelial cells into the lumen during lactation (7). Upon weaning, many MFGs remain in the lumen, and they seem to be engulfed by epithelial cells lining the lobules in the mammary gland (8). How these epithelial cells and macrophages recognize and engulf apoptotic cells and MFGs has not been well elucidated.Many molecules expressed on the surface of apoptotic cells or phagocytes have been proposed as ligands and receptors for the engulfment of apoptotic cells (9 -11). Mouse MFG EGF factor 8 (MFG-E8), called lactadherin in humans, is a 72-kDa glycoprotein s...

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Section: Discussionmentioning

confidence: 57%

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Hanayama

Nagata

2005

Proc. Natl. Acad. Sci. U.S.A.

120

118

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“…Experimental animal models have been invaluable in mammary gland research (reviewed in Hennighausen and Robinson, 2001), enabling the identification of mammary stem (Smalley et al, 2005;Shackleton et al, 2006;Stingl et al, 2006); and luminal progenitor cells (Sleeman et al, 2006(Sleeman et al, , 2007Asselin-Labat et al, 2007) and the molecular changes that are associated with the different phases of post-pubertal mammary development (Master et al, 2002;Clarkson et al, 2004;Stein et al, 2004). Mouse models displaying defects in these processes have also been very useful, for example, Gata-3, Elf-5 and Stat5a knockout mice have helped define the cellular events involved in the development of luminal and secretory cells, respectively (Asselin-Labat et al, 2007;Oakes et al, 2008;Yamaji et al, 2009), whereas PrlR and Gal knockout mice have shed light on the molecular events associated with the secretory activation stage of lactation (Naylor et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

et al. 2010

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Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitorlike expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1 Co/Co mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61 þ CD29 lo CD24 þ ) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.

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“…Genomic transcriptional profiling has been used recently to study the hairgrowth cycle and other cyclic processes, including the circadian rhythm and cycles in the female reproductive system such as mammary gland regulation (32)(33)(34)(35)(36)(37). We believe that our approach can be applied to time-course gene expression studies such as these to identify clusters of genes associated with a cyclic process of interest occurring in the context of a complex tissue.…”

Section: Genes Participating In Distinct Genetic Pathways Are Enrichementioning

confidence: 99%

Identification of hair cycle-associated genes from time-course gene expression profile data by using replicate variance

Lin

Chudova

Hatfield

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

106

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The hair-growth cycle is an example of a cyclic process that is well characterized morphologically but understood incompletely at the molecular level. As an initial step in discovering regulators in hair-follicle morphogenesis and cycling, we used DNA microarrays to profile mRNA expression in mouse back skin from eight representative time points. We developed a statistical algorithm to identify the set of genes expressed within skin that are associated specifically with the hair-growth cycle. The methodology takes advantage of higher replicate variance during asynchronous hair cycles in comparison with synchronous cycles. More than one-third of genes with detectable skin expression showed hair-cycle-related changes in expression, suggesting that many more genes may be associated with the hair-growth cycle than have been identified in the literature. By using a probabilistic clustering algorithm for replicated measurements, these genes were grouped into 30 timecourse profile clusters, which fall into four major classes. Distinct genetic pathways were characteristic for the different time-course profile clusters, providing insights into the regulation of hairfollicle cycling and suggesting that this approach is useful for identifying hair follicle regulators. In addition to revealing known hair-related genes, we identified genes that were not previously known to be hair cycle-associated and confirmed their temporal and spatial expression patterns during the hair-growth cycle by quantitative real-time PCR and in situ hybridization. The same computational approach should be generally useful for identifying genes associated with cyclic processes from complex tissues.H air-follicle morphogenesis starts late in embryogenesis and is completed on postnatal day (PN) Ϸ14 in mice ( Fig. 1 A and B). After this period of growth, which is referred to as anagen, hair-follicle cycling is initiated with a regression phase called catagen, in which the lower two-thirds of the hair follicle undergoes apoptosis (1). Subsequently, the regressed follicle enters a resting phase known as telogen. After this period of quiescence, anagen is initiated with the start of a new hairgrowth cycle (2). Cyclical growth of hair persists throughout postnatal life because of the regenerative capacity of hairfollicular stem cells (3, 4), which are believed to reside in the bulge region (Fig. 1 A) of the hair follicle. In mice, the first two hair-growth cycles occur in synchronized waves moving in an anterior-to-posterior direction. After the second cycle, synchronous hair growth occurs only in small patches (1), creating a mosaic pattern of hair follicles in different phases within the skin (Fig. 1C); overall, hair follicles are unsynchronized after the second cycle.Although a snapshot of gene expression in hair-follicle stem cells has been reported recently (5, 6), time-course profiling of all components of the skin is needed for comprehensive characterization of the complex molecular changes in hair-follicle development and cycling, which involves ...

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Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression

Cited by 302 publications

References 74 publications

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

Identification of hair cycle-associated genes from time-course gene expression profile data by using replicate variance

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