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Endocrinology, doi:10.1210/en.2003-1112
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Endocrinology Vol. 145, No. 7 3106-3110
Copyright © 2004 by The Endocrine Society

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Mammary Gland Branching Morphogenesis Is Diminished in Mice with a Deficiency of Insulin-like Growth Factor-I (IGF-I), But Not in Mice with a Liver-Specific Deletion of IGF-I

R. Gregg Richards, Diane M. Klotz, Michael P. Walker and Richard P. DiAugustine

Hormones and Cancer Group, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. Richard P. DiAugustine, National Institute of Environmental and Health Science, P.O. Box 12233, MD D4-04, Research Triangle Park, North Carolina 27709. E-mail: diaugus2{at}niehs.nih.gov.

Abstract

The development of the mouse mammary gland occurs postnatally. Hormonal activation of local growth factor pathways stimulates rapid elongation and branching of the rudimentary gland through the fatty stroma. Earlier studies showed that GH is required for mammary gland ductal morphogenesis and that IGF-I mediates this action of GH. In the present study we show that adult IGF-Im/m mutant mice exhibit a marked reduction in levels of mammary gland and liver igf1 transcripts compared with controls. Whole mounts of the adult IGF-Im/m mammary glands revealed ducts that extended to the limits of the fat pad; however, the number of bifurcation branch points in the ductal tree of the mutants was reduced by half compared with that of wild-type glands. In contrast, adult mutant mice with a liver-specific deletion of the igf1 gene obtained by Cre/loxP recombination strategy maintained the normal levels of mammary gland igf1 transcripts and did not exhibit a branching deficit in this organ. It was previously reported that this specific loss of liver IGF-I causes serum levels of IGF-I (endocrine) to decrease by approximately 75%, whereas the levels of tissue igf1 transcripts remain unchanged. On the basis of these findings, we propose that paracrine, not endocrine, IGF-I is important for mammary branching morphogenesis.

DEVELOPMENT OF THE mammary gland occurs in distinct stages, each requiring different hormonal and local factors. Estradiol (E2) and GH are important for the allometric development of the mouse mammary gland during the postnatal period, which is characterized by rapid elongation and ramification of the ducts throughout the fat pad (1). Different mutant mice have helped provide experimental models to determine the importance of various hormones and growth factors in mammary development. For instance, dwarf lit/lit mutants, which have very low serum levels of GH (2), exhibit a markedly reduced rate of postnatal ductal growth (3). Many of the postnatal effects of GH are considered to be mediated by IGF-I (4). The IGF-I-null mutant female mouse forms a mammary rudiment, but otherwise exhibits a very limited extension of the ducts into the fat pad despite having elevated levels of GH (5, 6). GH plus E2 do not stimulate mammary development in IGF-I-null mice in vivo, whereas treatment with the combination of des(1, 2, 3)IGF-I and E2 is effective in stimulating the number of ductal structures (5). In an organ culture system for mouse mammary glands, IGF-I stimulated ductal growth and elongation, whereas epidermal growth factor instead of IGF-I had no effect on ductal extension (7).

These data strongly suggest that an intact GH-IGF-I axis is important for postnatal formation of the mammary ductal tree. Stimulation of somatic growth was hypothesized to occur as a result of GH action on liver IGF-I synthesis (8), which is the major determinant of circulating (endocrine) IGF-I in normal animals. An alternative view holds that the majority of postnatal effects of GH are mediated by an increase in IGF-I synthesis in target organs to provide a paracrine stimulus (4); for example, GH can stimulate rat tibial bone growth without a corresponding increase in circulating IGF-I (9, 10). The normal mouse mammary gland expresses igf1 and igf1r transcripts in the mammary terminal end buds in virgin glands during the pubertal growth period (7). In accord with a paracrine-type mechanism, GH has been shown to elevate levels of IGF-I transcripts in the rodent mammary gland (11). In the present study we examine the mammary phenotype in different mutant mouse models. We chose the IGF-Im/m mouse (12) to determine whether a moderate deficiency (multiorgan) of IGF-I in an otherwise viable animal affects the normal patterning of mammary ductal morphogenesis. We also examined mammary glands from mice with a liver-specific igf1 gene deficiency (LID) achieved with the Cre/loxP system (13). This event causes circulating IGF-I levels to decrease by approximately 75% without a loss in growth or development. Together, these mutants provide an opportunity to gain insights into both the role and the source of IGF-I that functions in postnatal mammary gland development.

Materials and Methods

Animals and treatments
IGF-Im/m mutant mice were provided by Dr. Lyn Powell-Braxton (Genentech, Inc., San Francisco, CA) and bred on a C57BL/6 background at NIEHS, NIH. Female offspring from homozygous breeding pairs and age-matched controls (C57BL/6) were used as intact or ovariectomized animals. Beginning 2 wk after ovariectomy, which was performed between 24–27 d of age, animals received a daily sc injection of 1 µg E2 (Sigma-Aldrich Corp., St. Louis, MO) in sesame oil for a total of 14 d; controls received only sesame oil. Adult female LID mice were supplied by Dr. Derek LeRoith (NIDDK, NIH). All surgical and treatment procedures complied with the guidelines of the NIEHS, NIH, animal care and use committee. All mice that were housed at the NIEHS animal facility were exposed to a 12-h light, 12-h dark cycle and fed food and water ad libitum. Mice with an igf1-null mutation were generated from heterozygous breeding pairs provided by Dr. Argiris Efstratiadis (Columbia University, New York, NY). The dwarf (lit/lit) and control heterozygous (lit/+) mice were purchased from The Jackson Laboratory (Bar Harbor, ME).

Mammary gland whole mounts
The left inguinal mammary gland (no. 4) was spread onto a glass slide, fixed in a 1:3 mixture of glacial acetic acid/ethanol, hydrated, stained overnight in 0.2% carmine and 0.5% AlK(SO4)2, then dehydrated in graded solutions of ethanol, cleared in xylene, and mounted (14). Details of the quantitation of gland branching are given in Table 1Go.


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  		TABLE 1. Comparison of mammary ductal branching between IGF-I-deficient and control mice

 
RNA isolation and ribonuclease protection assays
Mammary glands and livers were resected, snap-frozen in liquid N2, and stored at –80 C. Total RNA was isolated with TRIzol (Invitrogen, Carlsbad, CA). RNA samples were hybridized with a 33P-labeled RNA probe complementary to nucleotides 73–487 of the reported mouse igf1 mRNA sequence (accession no. XO4482). This probe recognizes both A and B forms of igf1 mRNA. To normalize samples for loading, RNA was also hybridized with a 33P-labeled probe for mouse cyclophilin mRNA. Ribonuclease protection assays were performed with the RPA III Kit (Ambion, Inc., Austin, TX) according to the manufacturer’s instructions. Samples were electrophoresed in 6% polyacrylamide/7 M urea gels. The gels were then vacuum-dried and exposed to a phosphorimager screen, and the data were analyzed using a Storm 860 PhosphorImager (Molecular Dynamics, Sunnyvale, CA) as previously described (15).

Results and Discussion

The igf1m, or midi, allele was generated during an effort to create an igf1-null mouse (12). Instead of homologous recombination of exon 3, a site-specific intronic insertion of the targeting construct occurred. Mice homozygous for the igf1m allele (IGF-Im/m) are viable and fertile, but are growth retarded. The IGF-Im/m mice do produce wild-type IGF-I, but serum IGF-I levels in these mutants are reduced about 70% compared with wild-type values (12). Thus, it was reasonable to expect that igf1 mRNA in these mutants would be reduced in liver and other organs. As shown in Fig. 1AGo, adult IGF-Im/m mammary and liver levels of IGF-I transcripts, determined by ribonuclease protection assay, were less than those in control animals. To determine whether the igf1m allele influences formation of the mammary ductal tree, whole mounts of the IGF-Im/m and control (C57BL/6) mouse mammary glands were examined at different stages of development. At 24 d of age, IGF-Im/m glands (Fig. 2BGo) exhibited rudimentary ductal structures indistinguishable from those of age-matched wild-type mice (Fig. 2AGo). On d 42 (Fig. 2CGo), glands from wild-type mice exhibited ducts that extended well beyond the lymph node. In contrast, IGF-Im/m mammary glands at this age displayed fewer branching ducts, which did not extend as far into the fat pad as in control glands (Fig. 2DGo). By 70 d of age, the ducts in both groups had reached the limits of the fat pad (Fig. 2Go, E and F); however, the number of overall branch points in the mutant mice was approximately half that in wild-type animals (Table 1Go). As a comparable decrease was observed in the frequency of bifurcation points along the primary ducts of the IGF-Im/m mammary glands, it is possible that bifurcation is the major developmental event in the mammary gland affected by low IGF-I levels. This branching deficit in the mammary gland was still apparent in IGF-Im/m mice at 144 d of age (data not shown). The IGF-Im/m mutant mammary phenotype may result from impaired secretion of ovarian steroids. To address this concern, mice were ovariectomized prepubertally and then treated daily with E2 for 2 wk. These treatments stimulated branching morphogenesis beyond the lymph node in both the control and mutant groups. However, the IGF-Im/m mammary glands that formed during the period of hormone treatment developed with the same ductal branching deficit that is observed in the intact IGF-Im/m mouse (Table 1Go). These data indicate that impairment of ovarian estrogen secretion did not contribute to the IGF-Im/m mammary phenotype.



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  		FIG. 1. Expression of igf-1 mRNA in the mammary gland and liver of an IGF-Im/m mouse (A) and a mouse (LID) with a deletion of the liver igf1 gene (B). Total RNA from each organ was extracted and analyzed for igf1 transcript by the ribonuclease protection assay as described in Materials and Methods. The protected fragments representing igf1A, igf1B, and cyclophilin (cyc) mRNAs are indicated. The igf1A fragment was used for quantitation; levels of cyclophilin transcripts were used for normalization of the different samples. The gels shown in A and B represent one of the analyses of protected fragments from a control and a mutant mouse. The bar graphs represent the quantitation of igf1A for the corresponding lane corrected for cyclophilin (counts per minute of igf1A:counts per minute of cyc x 102). A, Mouse mammary and liver igf1 mRNA are reduced in mutant IGF-Im/m mice (n = 3) compared with that in control mice (C57/BL/6; n = 3). B, The deficiency of igf1 transcripts in LID mouse livers (n = 3 for mutant and controls) is evident, whereas mammary gland levels were not different from those in floxed controls (n = 3 for mutant and controls).

 


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  		FIG. 2. Whole mounts of inguinal mammary glands (no. 4) from young and adult female IGF-Im/m mice. Mammary rudiments (arrows) appeared similar in 24-d-old (d24) C57BL/6 (A) and IGF-Im/m (B) mice. At 42 d of age (d42), numerous branching ducts with terminal end buds extend just beyond the lymph node (ln) in the control gland (C), whereas IGF-Im/m glands (D) show fewer ducts extending to the ln. In 70-d-old IGF-Im/m mice (F), numerous ducts reach the limits of the fat pad, but display fewer branching structures than in control d70 mice (E). Bar, 1.0 mm (A–D), 3.0 mm (E and F).

 
Other studies also indicate that IGF-I is important for mammary ductal branching. When ovariectomized igf1-null mutant mice were treated with E2 for 2 wk, extension of the ducts into the fat pad was clearly greater than that in vehicle-treated, null mutants; however, virtually no branching was observed for those ducts that had further infiltrated the fat pad (data not shown). Grafting of the mammary gland is another experimental approach that has been used to resolve the function of IGF-I in this organ. When outgrowths from embryonic IGF-I receptor-null (igf1r–/–) mouse mammary glands were grafted into the cleared fat pads of syngeneic virgin recipients, the outgrowths exhibited limited ductal development compared with outgrowths from igf1r+/+ glands, especially with regard to the number of ductal branch points and terminal end buds (16). Additionally, mammary glands of C57BL/6J mice exhibit less ductal branching than C3H/HeJ mice (Bennett, L. M., unpublished observation). This difference between the mouse strains could be ascribed to IGF-I, because C3H mice have serum IGF-I levels 35% greater than those in C57 mice (17). As these serum IGF-I levels might also reflect strain-specific differences in tissue production of IGF-I, such findings do not reveal the relative contributions of endocrine and paracrine IGF-I to mammary development.

To address this issue, we examined mammary development in mice (LID) that have a marked reduction in serum (endocrine) IGF-I. Deletion of the liver igf1 gene by the Cre/loxP recombination strategy reduces serum IGF-I by nearly 75% without affecting postnatal body growth or IGF-I expression in other nonhepatic tissues (13). These findings support the idea that the liver is the major source of circulating IGF-I. We were able to use mammary glands from adult liver-specific IGF-I knockout mice in our experiments because the reduction of serum IGF-I in these mutants was achieved well before the beginning of ovarian hormone secretion and the allometric phase of mammary gland morphogenesis (13). When whole mounts of the mammary ductal tree of the LID mutants were compared with those of controls (Fig. 3Go), quantitative differences in the extent of branching points were not observed (Table 1Go). As shown in Fig. 1BGo, igf1 transcript levels in adult LID mammary glands were comparable to those in glands from floxed controls. The elevated level of serum GH that is known to occur in these mutants (13) did not increase the level of igf1 transcripts above that in controls. Thus, the phenotype of the LID mammary gland, as with other nonhepatic organs in this mutant, cannot be explained by a compensatory elevation of tissue IGF-I by GH.



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  		FIG. 3. Whole mounts of an inguinal mammary gland from an adult (90 d old) floxed control (A) and a mouse (LID) with a liver-specific deletion of the igf1 gene (B). The area shown is the midregion of the gland. Bar, 1.0 mm.

 
We also examined whole mounts of mammary glands from the aforementioned dwarf lit/lit mutant adult virgin female mice. We confirmed that the mammary ductal tree of the homozygote mutants was underdeveloped and only partially infiltrated the fat pad (3); however, the extent of branching for the limited amount of gland that did form in the mutant was similar to that in the heterozygote or wild-type controls (data not shown). Although GH is important to stimulate mammary development, the hormone may not specifically influence the extent of mammary branching in those cases where the local (paracrine) system for biosynthesis of IGF-I in this organ is not impaired. In addition, these findings suggest that animal body mass per se is not directly correlated with the extent of mammary ductal branching.

Our findings suggest that IGF-I is important for branching morphogenesis during pubertal development of the mammary gland and that the primary source of the growth factor for this function is paracrine, not endocrine. Although the IGF-Im/m and LID mutants exhibit a profound, if not similar, reduction in serum IGF-I compared with corresponding wild-type controls, it is the IGF-Im/m mouse with reduced tissue IGF-I, not the LID mouse, that reveals changes in mammary gland phenotype. The data do not allow us to exclude the possibility that there may be conditions in which serum IGF-I, especially as the free or unbound ligand, contributes to postnatal gland growth. Studies of mice with mutations that exclusively reduce circulating IGF-I derived from liver have revealed pronounced effects on bone architecture (18, 19). Unlike the LID animals, mice that are deficient for pancreatic endoplasmic reticulum eIF{alpha} kinase have a 75% reduction in liver igf1 mRNA and serum IGF-I within the first week of neonatal development. The reduction of serum IGF-1 during this period may account for the retardation of the longitudinal growth of the tibia and overall postnatal growth. The expression of igf1 mRNA in most other organs of this mutant remained normal (19).

The IGF-I system is currently considered to affect breast cancer susceptibility. In one study elevated circulating IGF-I levels were associated with an increased risk of breast cancer in premenopausal women (20). In addition, mammographic breast density, which is one of the strongest predictors of breast cancer (21, 22), was positively correlated with plasma IGF-I levels and inversely correlated with plasma IGF-binding protein-3 among premenopausal women (23). Although our data indicate that it is paracrine, not endocrine, IGF-I that is important for branching morphogenesis, the measurement of serum IGF-I may serve as a surrogate indicator of mammary IGF-I. This assumes a direct correlation between the activity of the GH-IGF-I axis in the liver and breast tissue of adult human females. A major query that remains is whether branching morphogenesis and breast density have homologous aspects that are determined by IGF-I. Understanding how the GH-IGF-I axis and IGF-I-related signaling pathways contribute to breast density and the etiology of breast cancer will be a critical research problem to pursue.

Acknowledgments

We thank Dr. Shoshana Yakar, Dr. L. Michelle Bennett, Mary Custer, John Couse, and Elizabeth Padilla-Banks for their assistance with these studies. We also thank Dr. Bonnie Deroo, Dr. Frank Kari, and Retha Newbold for their critical reviews of the manuscript.

Footnotes

Abbreviation: E2, Estradiol.

Received August 26, 2003.

Accepted for publication March 23, 2004.

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