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Endocrinology Vol. 141, No. 11 4278-4283
Copyright © 2000 by The Endocrine Society

ARTICLES

Glycosylation-Dependent Cell Adhesion Molecule 1 (GlyCAM 1) Is Induced by Prolactin and Suppressed by Progesterone in Mammary Epithelium1

Zhaoyuan Hou, Jason P. Bailey, Archie J. Vomachka, Manabu Matsuda, Jason A. Lockefeer and Nelson D. Horseman

Department of Molecular and Cellular Physiology (Z.H., J.P.B., A.J.V., M.M., J.M., J.A.L., N.D.H.), Department of Internal Medicine, Division of Endocrinology and Metabolism (N.D.H.), University of Cincinnati, Cincinnati, Ohio 45267; Department of Biology (A.J.V.), Beaver College, Glenside, Pennsylvania 19038

Address all correspondence and requests for reprints to: Nelson D. Horseman, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0576. E-mail: nelson.horseman{at}uc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Glycosylation-dependent cell adhesion molecule 1 (GlyCAM 1), a mucin-like endothelial glycoprotein, was induced by PRL and suppressed by progesterone in the mammary gland of mice, and in HC11 mouse mammary epithelial cells. Complementary DNA microarray analysis revealed that expression of GlyCAM 1 was reduced in the mammary gland of PRL-gene disrupted mice (PRL-/-) compared with control (PRL+/-) littermates. This result was confirmed by in situ hybridization and immunostaining. The messenger RNA (mRNA) encoding GlyCAM 1 was present in mammary epithelia of PRL-stimulated mice. Immunohistochemistry indicated that GlyCAM 1 protein was detectable both in mammary epithelia and in the ductal lumen in PRL+/- virgin mice, but not in PRL-/- mice. GlyCAM 1 mRNA was highly induced by grafting pituitary glands from normal littermates. Trace amounts of mRNA for GlyCAM 1 were detected by RT-PCR in mammary tissue of PRL-/- mice. Progesterone inhibited both basal and PRL-stimulated GlyCAM 1 transcription. In HC11 cells, GlyCAM 1 mRNA was induced in cells treated with insulin, dexamethasone, and PRL. Similar to the in vivo studies, progesterone inhibited the induction of GlyCAM 1 transcription. In CHO cells, PRL stimulated transcription of a luciferase reporter gene containing an 800-bp promoter fragment of GlyCAM 1, and progesterone partially suppressed the PRL effect. These data demonstrate that expression of GlyCAM 1 in mammary gland is under the control of both PRL and progesterone.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GLYCOSYLATION-DEPENDENT cell adhesion molecule 1 (GlyCAM 1) was identified as a mucin-like endothelial glycoprotein, which is secreted into the high endothelial venules (HEV) of peripheral and mesenteric lymph nodes. GlyCAM 1 functions as a ligand for L-selectin and mediates the trafficking of blood-born lymphocytes into secondary lymph nodes (1, 2, 3). GlyCAM 1 is also expressed in pregnant and lactating mammary glands of mouse and cow (4, 5), in lung, uterus (6), and cochlea (7). However, the functions and hormonal control of GlyCAM 1 in these tissues are not known.

Previous studies implied that the expression of GlyCAM 1 in these divergent tissues might be regulated by different mechanisms (4). GlyCAM 1 is highly expressed in HEV of lymph nodes and apparently affected by afferent lymphatic flow, and because ligation of afferent lymphatics results in a complete loss of the messenger RNA (mRNA) for GlyCAM 1 (2, 3). In the mammary gland, the expression pattern of GlyCAM 1 is similar to that of milk proteins, being induced during pregnancy and lactation. However, the mRNA level of GlyCAM 1 in the inguinal lymph nodes adjacent to lactating mammary glands showed no similar induction (4). These observations indicated that GlyCAM 1 in secondary lymph nodes and in mammary glands might be regulated differently. Recent studies revealed that the level of GlyCAM 1 mRNA and protein in ovine uterus closely parallels changes in progesterone receptor expression in endometrial epithelia during the estrous cycle, which suggested that progesterone may be a potential regulatory factor for GlyCAM 1 in uterus (6).

The potential functions and regulation of GlyCAM 1 in these divergent organs raise intriguing questions. However, the factors that directly regulate GlyCAM 1 expression have not yet been identified.

PRL is a peptide hormone secreted by anterior pituitary gland, which exerts pleiotropic physiological effects in various cells and tissues (8). In the mammary gland epithelium PRL stimulates alveolar growth and cellular differentiation and participates in lactation by initiating and maintaining milk protein synthesis (9, 10). By screening for differentially expressed genes in mammary glands of PRL-gene disrupted (PRL-/-) mice using a complementary DNA (cDNA) expression array, it was found that the expression level of GlyCAM 1 was reduced in PRL-/- mouse mammary glands. Further studies indicated that GlyCAM 1 was induced by PRL and suppressed by progesterone in both mammary glands and cultured mammary epithelial cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
PRL-/- mice were described previously and maintained in the University of Cincinnati Animal Care Facility (10). The surgeries and other procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee. Donor pituitaries were harvested from littermate PRL+/- females, and inserted under the kidney capsule of recipients. The viability of grafts was confirmed by immunostaining the graft sites with antimouse PRL antibody. Implantation of progesterone pellets (Innovative Research of America, Sarasota FL; 25 mg/pellet) was described previously (11).

cDNA expression array
Atlas cDNA expression arrays were purchased (CLONTECH Laboratories, Inc., Palo Alto, CA), and hybridization was performed following the manufacturer’s instruction. Briefly, mammary glands (without the resident lymph node) were collected from 10-week-old mice, and total RNA was extracted with TRI Reagent (MRC, Inc., Cincinnati, OH). The RNAs were treated with RNase-free DNase (Roche, Indianapolis, IN) and purified with phenol-chloroform extraction. Poly +A RNA was isolated with CHROMA SPIN-200 DEPC-H2O column (provided in the kit). {alpha}-p32-dATP was purchased from Amersham Pharmacia Biotech, and cDNA was synthesized with MMLV Reverse transcriptase. Hybridization was done following the manufacturer’s instruction and the membranes were exposed to BioMAX films.

In situ hybridization and immunostaining analysis
A 197-bp PCR fragment of GlyCAM 1 was subcloned into pGEM II vector, which was linearized with NcoI and SalI. The digoxigenin-labeled RNA probes were made using T7 and SP6 RNA polymerases (DIG RNA labeling kit, Roche, Indianapolis, IN). Mammary tissues from 10-week-old mice were fixed in 4% paraformaldehyde for 6–8 h and then soaked in 30% sucrose in PBS overnight. The tissues were embedded in M1 medium and frozen in liquid nitrogen. The tissue blocks were sectioned by Cryostat at a thickness of 10 microns. The sections were processed and hybridization was performed according to Tsukamoto, et al. (12). Hybridized DIG-RNA probes were detected using Anti-DIG detection kit (Roche, Indianapolis, IN) following the recommended protocol in the kit.

Immunohistochemistry was performed on frozen sections using HistoMOUSE SP kit (Zymed Laboratories, Inc., San Francisco, CA). Anti GlyCAM 1 antibody CAM02 was kindly provided by Dr. Singer. The antibody was diluted to 1:1000 in PBS. Photographs were taken using Olympus Corp. (Tokyo, Japan) BL60 microscope with attached Spot2 digital camera.

Cell culture
CHO K1 cells were maintained in Ham’s F12 medium (Life Technologies, Inc., Rockville, MD) with 1x antibiotic/antimycotic (Life Technologies, Inc.), and 10% FBS (13).

HC11 cells were cultured with RPMI-1640 medium with 10% heat inactivated FCS, 5 µg/ml insulin, 10ng/ml epidermal growth factor, and 1% penicillin-streptomycin (14). The cells were kept for 2 days at confluency before switching to serum-free medium. For induction, cells were cultured in medium containing I (insulin, 5 µg/ml) only, or I + Dex (dexamethasone, 10-6 M) or I + PRL (ovine PRL, 1 µg/ml), or I + Dex + PRL, or I + Dex + PRL + Pg (progesterone, 10-7 M), or I + Dex + Pg, or I + Pg for 48 h. The cells were harvested and total RNAs were isolated with TRI Regent (MRC, Cincinnati, OH) and treated with RNase-free DNase, and then purified with RNeasy RNA purification kit (QIAGEN, Valencia, CA). The quality of total RNA was checked by agarose gel and the concentration was determined by spectrophotometer.

RT-PCR
cDNAs were synthesized using AMV reverse transcriptase (Life Technologies, Inc.). The GlyCAM 1 primers for PCR amplification were: forward primer 5'-GTGCCACCATGAAATTCTTC-3' and reverse primer 5'-TCTTCATGACTTCGTGATAC-3'. The resulting fragment from GlyCAM 1 cDNA was 467 bp (15). The program for PCR was 94 C for 3 min, one cycle; 94 C for 30 sec, 60 C for 30 sec and 72 C for 1 min for 30 cycles. GAPDH primer: forward primer 5'-TCGTCCCGTAGACAAAATGGT-3' and reverse primer 5'-TCGCTCCTGGAAGATGGTGATG-3' were used as an internal control and PCR product was 251 bp.

Luciferase reporter assay
An 800-bp promoter region of GlyCAM 1 including part of exon 1 was cloned into pGL3 vector to make the GlyCAM 1-Luc reporter construct. This promoter fragment contains four potential GAS (interferon-{gamma} activated sequence) sites (see Fig. 6AGo), and several GRE (glucocoticoid response element) consensus sequences. Construction of PRL receptor plasmids and ß-galacatosidase plasmids were described previously (13, 16). At 24 h before the transfection CHO K1 cells were plated out at 2 x 106 cells per 35-mm plate. Transfections were carried out using the Fugene 6 Transfection Agent (Roche, Indianapolis, IN). Cells were cotransfected with 0.5 µg cytomegalovirus ß-gal construct, 2 µg GlyCAM 1-Luc reporter construct, and 2 µg pigeon PRL receptor plasmid. Four hours after addition of DNA cells were washed twice with 1x PBS and changed to serum-free media either with or without 1 µg/ml ovine PRL (oPRL) and progesterone (10-7 M). Cells were maintained in serum-free media for 36 h and then harvested using the lysis buffer from Luciferase Reporter Gene Assay Kit (Roche, Indianapolis, IN) according to manufacturer’s protocol. Five microliters of cell extract was used for the ß-gal assay, which was performed according to the manufacturer’s protocol (Tropix, Bedford, MA). Amounts of cells extracts used were standardized to the ß-gal activities and the Luciferase assay was performed according to the manufacturer’s protocol (Roche, Indianapolis, IN).



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  		Figure 6. PRL drives and progesterone suppresses transcription of the luciferase reporter gene in pGL3 vectors containing an 800bp fragment of GlyCAM 1 promoter. A, Map of mouse GlyCAM 1 promoter showing the location and sequences of potential GAS elements. B, Relative luciferase activities following treatment of transiently transfected CHO K1 cells with hormones.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
cDNA expression array assay for potential PRL- dependent genes
PRL-/- mice have been developed and characterized (10, 11). To identify genes downstream of PRL signaling, cDNA expression array analysis was performed on the mammary gland tissues from PRL-/- and control mice (PRL+/-), and on pituitary grafted and progesterone treated PRL-/- mice. Analyses of the array results for comparison between PRL+/- and PRL-/- mice are summarized in Table 1Go. Among the genes identified, GlyCAM 1 expression was substantially reduced in PRL-/- mice mammary glands (Fig. 1Go). This observation was taken as the basis for studying the details of GlyCAM 1 regulation in the mammary gland.


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  		Table 1. Statistical summary of mRNA expression profile comparison of mammary glands from normal control (PRL+/-) and PRL knockout (PRL-/-) mice

 


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  		Figure 1. GlyCAM 1 expression was substantially reduced in PRL-/- mouse mammary glands by Atlas Mouse cDNA expression arrays analysis. The film was developed for 1 week at -70 C. The location of GlyCAM 1 in the array map is F1i, and keratin 18 and 19 are F5i and F5j, respectively. The arrows show their locations. A, PRL+/-, B: PRL-/-.

 
The morphological differences between mammary glands of PRL-/- and PRL+/-mice might cause apparent differences in gene expression that were a consequence of the relative increase in epithelial cell numbers in PRL+/- mice compared with PRL-/- mice (10). To avoid this source of bias, cytokeratin 18 and 19 (epithelial markers) were compared (Fig. 1Go). Based on analyses of the array hybridization, mammary tissues were studied by in situ hybridization and immunostaining to definitively test the apparent PRL-dependent expression of GlyCAM 1.

Localization and regulation of GlyCAM 1 gene expression in vivo
In situ hybridization using antisense GlyCAM 1 cRNA probe showed that the GlyCAM 1 gene was expressed in mammary epithelia in normal nulliparous females (Fig. 2Go). In mammary tissue of PRL-/- mice GlyCAM 1 mRNA appeared to be confined to a small number of cells that may be endothelium or myoepithelium in contrast with the pattern of expression in epithelium of PRL+/- mice. The low level of GlyCAM 1 mRNA in the PRL-/- mammary glands was confirmed by RT-PCR (Fig. 4Go). Immunostaining of mammary gland frozen sections indicated that GlyCAM 1 protein was detectable in both the mammary epithelium and in the lumen of PRL+/- virgin mice. No GlyCAM 1 protein was detected in mammary glands of PRL-/- mice (Fig. 3Go). Previous studies indicated that GlyCAM 1 was a secreted protein, and existed in the lumen of HEV, serum and in the whey fraction of milk (1, 3, 17).



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  		Figure 2. The mRNA of GlyCAM 1 was localized to mammary epithelia, and expressed in a PRL-dependent manner. DIG-labeled GlyCAM 1 cRNA was probed and signal was developed with NBT/BCIT substrate. A and B, Inguinal lymph node; C, D, E and F: inguinal mammary tissue. A, C, and E: PRL-/-; B, D and F, PRL+/-.

 


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  		Figure 4. GlyCAM 1 mRNA was highly induced by grafting pituitary glands from normal littermates and suppressed by treated with progesterone. Lane 1, PRLminus]/- mouse; lane 2, PRL-/- mouse treated with pituitary grafting; lane 3, PRL-/- mouse treated with progesterone pellet; lane 4, PRL-/- mouse treated with both pituitary grafting and progesterone pellet.

 


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  		Figure 3. GlyCAM 1 protein was detectable in both mammary epithelia and the lumen of PRL+/- virgin mice, but not in PRL-/- mice. A and B, Inguinal lymph node; C and D, inguinal mammary tissue. A and C, PRL-/-; B and D, PRL+/-.

 
In situ hybridization and immunostaining showed that high levels of GlyCAM 1 mRNA and protein were localized to the HEV of the resident lymph node in the inguinal mammary gland. The signals were very strong in the HEV in both PRL+/- and PRL-/- mice and there was no apparent difference (Figs. 2Go and 3Go). This implies that GlyCAM 1 is regulated differently in HEV and mammary epithelium, with PRL being essential for high expression in the mammary gland.

To study the in vivo induction of GlyCAM 1 by PRL, mature PRL-/- mice (10 weeks old) were grafted with pituitary glands from PRL+/- littermates (11). For comparison, some PRL-/- mice were treated with progesterone, while some were treated with both progesterone and pituitary grafting. After 18 days, inguinal mammary glands were collected and total RNAs were extracted. RT-PCR analysis showed that GlyCAM 1 mRNA was highly induced by pituitary grafting (Fig. 4Go). Interestingly, little to no GlyCAM 1 mRNA was detected by RT-PCR in the mammary gland of PRL-/- mice treated with progesterone only, or in those treated with progesterone and pituitary grafting.

PRL and dexamethasone synergistically induce endogenous GlyCAM 1 transcription in HC11 cells
The HC11 cell line was derived from the BALB/c mouse mammary epithelial cell line COMMA-1D and is unique in maintaining the ability to produce the major mouse milk protein ß-casein under the tight control of lactogenic hormones. PRL can induce the transcription of the endogenous ß-casein gene in HC11 cells (18). Therefore, we asked whether PRL is able to induce the endogenous GlyCAM 1 mRNA in HC11 cells. Two-day confluent HC11 cells were treated with serum-free media containing different hormone combinations (Fig. 5Go). The expression of GlyCAM 1 mRNA was assayed by RT-PCR, which showed that GlyCAM 1 mRNA was detected in cells treated with insulin, dexamethasone and PRL. Similar to the result of the in vivo assay, progesterone inhibited the induction of GlyCAM 1 in HC11 cells (Fig. 5Go). The PCR fragment was cloned and sequenced to confirm the specificity of PCR amplification (data not show).



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  		Figure 5. PRL and dexamethasone synergistically induce endogenous GlyCAM 1 transcription in HC11 cells. Lane 1, I only; lane 2, I + Dex; lane 3, I + PRL; lane 4, I + Dex + PRL; lane 5, I + Dex + PRL + Pg; lane 6, I + Dex + Pg; and lane 7, I + Pg.

 
The GlyCAM 1 promoter is transcriptionally controlled by PRL and progesterone
An 800-bp fragment of the GlyCAM 1 promoter including part of exon 1 was cloned into the pGL3 luciferase reporter gene vector (Fig. 6AGo). This promoter fragment contains four apparent GAS sites, which may bind Stat proteins and mediate PRL responsive gene transcription (19), and several GRE consensus sequences (20). CHO cells have all the necessary components for PRL signaling except the PRL receptor, and constitutively express glucocorticoid receptor. These cells have been used successfully to study lactogenic hormone interactions after being transfected with plasmids encoding the PRL receptor (13, 16). PRL stimulated the transcription of GlyCAM 1-Luc by about 3.0-fold (Fig. 6BGo). This induction was PRL receptor-dependent. Cells without cotransfection of PRL receptor showed no induction by PRL (data not show). Coincubation with progesterone suppressed GlyCAM-Luc activity by approximately 50% (Fig. 6BGo).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The function of GlyCAM 1 in mammary gland is still unknown. In lymphoid organs, GlyCAM 1 protein may be a signaling molecule, and it can bind to L-selectin and facilitate blood borne lymphocytes trafficking into HEVs of secondary lymph nodes (1, 17). The mammary GlyCAM 1 molecule lacks the sulfate modification required for L-selectin binding, and does not interact with L-selectin-IgG chimera (4, 17). Dowbenko et al. (4) postulated that the milk GlyCAM 1 might function in the gastrointestinal tract of the pup as a lubricant, or to protect the lining of these organs from colonization by pathogens. In this report, the detection of GlyCAM 1 molecule in virgin mice mammary gland may broaden the putative functions of this molecule in the mammary gland. During breast development, GlyCAM 1 may assist branching and alveologenesis. In this case, GlyCAM 1 would function in a manner similar to surfactant proteins in lung alveologenesis (21). In a recent report, it was hypothesized that GlyCAM 1 may be involved in conceptus-maternal interactions during the peri-implantation period of pregnancy in sheep (6).

The data reported herein clearly demonstrate that expression of GlyCAM 1 in mouse mammary gland is under the control of both PRL and progesterone. PRL increases the transcription rate of GlyCAM 1 in the mammary gland, while progesterone inhibits GlyCAM 1 transcription. Therefore, the highest GlyCAM 1 synthesis occurs during lactation, when PRL is secreted at a high level and progesterone is low (4). Analysis of the 5' flanking region of the GlyCAM 1 genomic sequences revealed that there are several potential glucocorticoid and/or progesterone receptor binding sites and GAS sites (20, 22, 23). Stat5, the primary signal transducer for the PRL signaling pathway, can bind to the GAS site and initiate PRL-dependent gene expression (19). The 800-bp fragment of GlyCAM 1 promoter containing four GAS sites is responsive to PRL induction (Fig. 6Go). However, the potential role of individual GAS sites needs to be dissected further. In CHO cells, progesterone was able to suppress GlyCAM-Luc activity, even in the presence of PRL. These data suggest that suppression of GlyCAM 1 transcription by progesterone is an independent event, and there may exist progesterone responsive elements in the promoter region of GlyCAM 1 gene. Additional regulatory elements likely exist outside the 800-bp promoter fragment that we have thus far assayed because progesterone partially suppressed the PRL effect in CHO cells.

Previous studies demonstrated that PRL and glucocorticoid synergistically induce expression of ß-casein gene expression in HC11 cells (14). In the present studies, PRL and glucocorticoid showed a similar synergistic relationship during induction of GlyCAM 1 transcription in HC11 cells. GlyCAM 1 mRNA is induced in cells treated with PRL and dexamethasone but not in cells treated with PRL or dexamethasone individually. On the contrary, progesterone does not show such synergism, and inhibits the inducing effect of PRL on GlyCAM 1 expression. One possible explanation of this result is that binding of progesterone to its receptor might interrupt the synergistic interaction between glucocorticoid receptor and Stat5 (24).

In secondary lymphoid organs GlyCAM 1 may be regulated by different factors. GlyCAM 1 is highly expressed in the HEV of the resident lymph node in the inguinal mammary gland, and not affected by PRL gene disruption. Similar observations have been reported (4). These data imply that PRL may not be a key player in the regulation of GlyCAM 1 in the secondary lymph nodes.

Interestingly, GlyCAM 1 mRNA was detectable in PRL-/- mice apparently in nonepithelial cells (Fig. 2Go). This basal expression was also suppressed by progesterone treatment. These data indicate that PRL is not the only factor regulating GlyCAM 1 transcription in vivo. Analysis of the 5' flanking region of the GlyCAM 1 genomic sequences showed that besides the GAS sites and GREs, there are other cis-response elements such as AP-1 sites, NF-1 sites, etc. These elements may responsible for the basal expression of GlyCAM 1 mRNA in PRL-/- mice (25).

Although a great deal is known about milk protein gene expression in the breast, there is very little information about how PRL promotes development, and specifically how the mammary ducts undergo the process of alveologenesis. The discovery of genes that are regulated by PRL in nonpregnant animals will provide new information about gene expression and mammary morphogenesis.


   Acknowledgments
 
The authors thank Dr. Mark S. Singer for providing GlyCAM 1 antibody and Ms. Meena J. Mistry and Juxian Mao for kind assistance on cell culture.


   Footnotes
 
1 This work was supported by National Institutes of Health. Back

Received May 16, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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