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Insulin-Like Growth Factor I Is Essential for Terminal End Bud Formation and Ductal Morphogenesis during Mammary Development¹

Departments of Medicine, New York University School of Medicine, and Department of Veterans Affairs Medical Center, New York, New York 10010

Address all correspondence and requests for reprints to: David L. Kleinberg, M.D., New York School of Medicine, Room 16043W, 423 East 23rd Street, New York, New York 10010. E-mail: kleind02{at}popmail.med.nyu.edu

	Abstract

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Previous studies from this laboratory have emphasized the essential role of GH in pubertal mammary development and shown that insulin-like growth factor I (IGF-I) was capable of substituting for GH in this process in rats and mice. The present study shows that, even when GH is present, no mammary development is possible unless IGF-I is present. IGF-I^(-/-) null female animals were found to have significantly less mammary development than age matched wild-type controls (P <0.006) using several endpoints including the number of terminal end buds or TEBs (1.3 vs. 7.3), percent of the fat pad occupied by glandular elements (6.5 vs. 100), and number of ducts (15 vs. too numerous to count). That the deficiency in mammary gland development was related to the absence of IGF-I was underscored by the observation that des (1–3) IGF-I administration to IGF-I^(-/-) null animals for 5 days caused significant mammary gland development as measured by TEB formation and branching of ducts. The number of TEBs rose from a mean of 1.3 in controls to 20.5 without added E₂ (P < 0.009), and from 1.7 to 21 when des (1–3) IGF-I was given together with E₂ (P < 0.006). The number of ducts increased significantly from a mean of 12 to 27 in response to IGF-I and E₂, and from 15 to 24.5 with IGF-I alone. In contrast, administration of human GH with E₂ had no stimulatory effect on mammary development in these animals, indicating that the full effect of GH in this process is mediated by IGF-I.

To determine whether IGF-I was also responsible for further ductal morphogenesis, we administered des (1–3) IGF-I + E₂ to the knockout animals for 14 days and compared the effects of this combination of hormones on mammary development with those observed after 5 days. We found that there was a significant increase from 5 to 14 days in the number of TEBs (mean: 21 vs. 41) and the area of the mammary fat pad occupied by glands (mean: 10 vs. 20%). There was elongation and thickening of the ducts which accounted for the increased area that was occupied by ductal structures. There was no significant increase in the number of ducts. However, there was the appearance of a large number of buds along the length of the ductal structures, suggesting the beginning of side branching. These results suggest that IGF-I, when given along with E₂, is responsible for ductal morphogenesis.

	Introduction

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THE COMPLEXITY OF the hormonal control of the development of the mammary gland has only recently begun to be understood. While mammary development has long been known to be under the control of pituitary and ovarian hormones (1, 2), the mechanisms of action of some of the hormones involved have not been well understood. Advances in molecular biology and development of special animal models have made possible an in-depth understanding of these mechanisms. The present paper is about the roles of insulin-like growth factor I (IGF-I) and GH in mammary development during puberty.

In recent years, we have shown that GH is as essential for mammary development as is estrogen (3, 4) and have, therefore, postulated that understanding the mechanism by which GH exerts its control would eventually lead to the design of novel treatments for breast cancer. We found that GH acted through the GH receptor (4), probably in the stromal compartment of the mammary gland (5), to stimulate IGF-I messenger RNA (mRNA) production (4, 5, 6). Although we have previously presented strong indirect evidence that local production of IGF-I mediates the action of GH in inducing terminal end bud (TEB) formation, the structures through which all mammary development takes place (6, 7), we have not yet provided direct proof that IGF-I is fully or partially responsible for mediating the effects of GH in early pubertal mammary development. Nor have we assessed a possible role for IGF-I in ductal morphogenesis. In this paper, we present proof that IGF-I fully mediates the action of GH in TEB development. We further demonstrate that the process of ductal morphogenesis is also controlled by IGF-I with estrogen.

	Materials and Methods

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Animals
IGF-I^(-/-) null animals were bred in our laboratory. Male mice that were heterozygous^(-/+) for IGF-I were mated with 8-week-old CD1 female mice (Charles River Laboratories, Inc., Wilmington, MA) to provide heterozygous animals for mating. One heterozygous male was placed in a cage with one or two heterozygous females. Although one expects 25% of the animals to be completely devoid of the gene for IGF-I, only approximately 1–2% of the knockouts survive. Of those, 66% were males and 34% were females. Wild-type female animals weighed a mean of 26 g vs. 6.8 g in the knockouts (P < 0.001) The animals were housed in sterile cages and sterile technique was used for their handling. The presence or absence of the IGF-1 gene was confirmed by PCR on DNA extracted from mouse tails as previously described (8, 9).

Treatment with hormones
Hormone treatment was begun at 42 days of age, so that examination of the mammary gland could be carried out at 47 days. IGF-I (20 µg; a gift Genentech, Inc., South San Francisco, CA) and human GH (hGH) (20 µg; a gift of Genentech, Inc.) were administered by Alzet model 1007D miniosmotic pumps (Alza Corp., Palo Alto, CA). These pumps were designed to deliver hormone or growth factor over a period of 5 days at 0.5 µl/h. Estradiol (E₂) (Calbiochem, La Jolla, CA) was given by SILASTIC brand capsule (Dow Corning, Midland, MI) implanted sc, as previously described (7).

Baker et al. (9) reported that mean E₂ concentrations were 57 pg/ml in wild-type animals vs. 30 pg/ml in IGF-I knockouts at 3 months of age. We attempted to give a close to physiological concentration of E₂ for wild-types to knockout animals by reducing the length of the SILASTIC brand silicon tubing by over 80%, but still serum E₂ concentrations at the end of experiments revealed that E₂ concentrations were higher than physiological (mean: 484 pg/ml). These elevated concentrations of E₂ had no stimulatory effect on mammary development in IGF-I^(-/-) null controls.

Under anesthesia, 42-day-old mice had SILASTIC brand capsules and miniosmotic pumps containing hormone, growth factor, or vehicle in controls implanted sc. A group of animals that did not receive E₂ served as controls, and another received des (1, 2, 3) IGF-I without E₂. After 5 days, animals were killed, mammary glands removed, and blood was collected. In another subset of experiments, miniosmotic pumps containing des (1, 2, 3) IGF-I (20 µg) were changed after 7 days so that animals were exposed to these hormone combinations for a total of 14 days.

Analysis of mammary gland development
Mammary development was examined in whole mount under a dissecting microscope (Nikon SMZ-U, Melville, NY) by: 1) counting TEBs, 2) measuring the area of the mammary fat pad occupied by glandular elements, and expressed as a percentage, and 3) counting the number of ducts. This analysis was done according to methods previously described for mammary development in hypophysectomized, oophorectomized rats (5, 6, 7).

	Results

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Mammary development in IGF-I deficient female mice
To determine whether IGF-I was essential for mediation of the action of GH in the process of pubertal mammary development, we studied mammary development in IGF-I^(-/-) null female mice. We postulated that, if IGF-I was the sole mediator of GH in mammary development, mammary gland architecture would be at least as impaired in these IGF-I-deficient animals as it is in hypophysectomized animals. Indeed, we found that mammary gland development in these IGF-I ^(-/-) animals was very significantly impaired when compared with mammary development in age-matched wild-type littermates, both with regard to the number of terminal end buds and the percent area of the mammary fat pad that was occupied by ductal and other glandular elements (Fig. 1 and Table 1). The total area of the mammary gland was 2.75 cm² in wild-type controls vs. 1.0 cm² in IGF-I^(-/-) null animals (P < 0.002).

View larger version (106K): [in this window] [in a new window]   Figure 1. Whole mounts of mammary glands from a 47-day-old wild-type mouse (upper panel) and an IGF-I(-/-) knockout (lower panel) female mouse (Magnification, 1.9x). Note that larger fat pad in the wild-type (WT) gland is fully occupied by glandular elements, whereas only 2 small areas of glands are found in the knockout (KO) animal.

Furthermore, little or no mammary gland development was noted in IGF-I^(-/-) null female animals after treatment with a combination of estradiol and hGH, in concentrations that would have been highly effective in stimulating mammary development in hypophysectomized oophorectomized animals (Table 2, Fig. 2). In contrast, Table 2 and Fig. 3 show that the combinations of des (1, 2, 3)-IGF-I and E₂ caused highly significant mammary development as evidenced by an increase in the number of TEBs, an increase in the percent of the total mammary fat pad occupied by glandular elements, and an increase in the total number of ducts in each gland.

View larger version (141K): [in this window] [in a new window]   Figure 2. The appearance of a gland from an IGF-I (-/-) knockout animal treated with hGH (20 µg) + E2 (upper panel) is not different than those given E2 alone (lower panel). (Magnification, 7.5x.)

View larger version (139K): [in this window] [in a new window]   Figure 3. Higher magnification (7.5x) of representative mammary glands from IGF-I (-/-) knockout animals. The gland in the upper panel comes from an animal treated for 5 days with E2 + des (1 2 3 ) IGF-I (20 µg), whereas the one in the lower panel comes from an animal treated with) E2 alone. Note the further extension of glandular elements into the substance of the mammary fat pad led by structures called terminal end buds (TEBs) in the animal receiving IGF-I. The number of TEBs in the IGF-I treated gland is 17 vs. 3 in the gland from the animal treated with E2 alone.

Effect of IGF-I on ductal morphogenesis
To determine whether the effect of IGF-I and E₂ was merely on formation of TEBs or whether further ductal morphogenesis, expected at puberty, was also controlled by IGF-I and E₂, we administered des (1, 2, 3) IGF-I and E₂ for a longer period of time (14 days instead of 5 days). After 14 days, we found that there was a further increase in the number of TEBs in comparison to animals treated for only 5 days (41 vs. 21; P < 0.008) and that the percent area of the gland occupied by ductal elements was double that reached at 5 days (Table 3; Figs. 4 and 5; P < 0.02). However, the actual number of ducts was not significantly increased. The ducts became longer, as can be seen in Fig. 4, accounting for the increased area of the mammary fat pad occupied by glandular elements. There was the appearance of bud-like structures in the elongating ducts and evidence of new branches arising from main ducts in the glands of animals (Fig. 4). The two-dimensional size of the mammary gland in whole mount did not increase during treatment with IGF-I and E₂; only the glandular elements changed.

View larger version (117K): [in this window] [in a new window]   Figure 4. Representative photomicrographs (magnification, 5x) of mammary glands from an animal treated with des (1 2 3 ) IGF-I + E2 for 5 days (upper panel) and another treated with the same hormones for 14 days. Note that the area of ductal morphogenesis is almost twice that in the mammary gland having been given hormone therapy for the longer period. The gland in the upper panel (5 days) has 17 TEBs, and glandular elements occupy 9% of the total area of the gland, whereas the one in the lower panel (14 days) has 30 TEBs and glandular elements occupy 24% of the total area of the gland fat pad. The arrows point to branching buds arising from the ducts.

View larger version (33K): [in this window] [in a new window]   Figure 5. Comparison of effect of E2 alone or E2 with des (1 2 3 ) IGF-I for either 5 days of treatment or 14 days of treatment on ductal morphogenesis.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Although GH and IGF-I are capable of independently inducing some mammary development in hypophysectomized, oophorectomized, sexually immature female rats (6), and E₂ in the absence of GH or IGF-I has no independent effect on mammary development, estrogen must be present for full development to take place. In fact, it is the estrogen surge in prepuberty that starts the process of mammary development (1, 12). One might even think of GH and IGF-I as factors that permit E₂ to act. In the present study, the E₂-containing SILASTIC brand capsules produced supraphysiological concentrations of E₂. To make certain that these higher than expected concentrations of E₂ did not alter our conclusion that IGF-I is essential for mammary development, we carried out experiments in which IGF-I was given to IGF-I^(-/-) null animals without additional E₂. We found that des (1, 2, 3) IGF-I alone was as effective as the combination of des (1, 2, 3) IGF-I + E₂ in stimulating mammary glandular development. As IGF-I^(-/-) null animals produce estrogen endogenously (9), we concluded that the estrogen already present was sufficient to allow synergy between it and IGF-I in the process of TEB formation, and that the supraphysiological concentrations of E₂ that the animals were exposed to had neither an inhibitory or further stimulatory effect over and above that of the endogenous estrogen in these animals.

We did not do oophorectomies or hypophysectomies in the IGF-I knockout animals because of their size, and therefore did not control for a possible effect of IGF-I on ovarian or pituitary function. However, we have done previous studies on hypophysectomized, oophorectomized, sexually immature Swiss Webster mice. We found that, as in rats, E₂ alone had no effect on TEB development after 5 days of treatment (mean number of TEBs 1.4 in controls vs. 2.0 in E₂-treated animals). In contrast, the combination of des (1, 2, 3) IGF-I (14 µg/pellet) and E₂ significantly increased TEB number to a mean of 22.3 (11).

Until now, our primary endpoint of mammary development has been formation of TEBs. These multilayered structures in which active cell division takes place are the structures that lead the entire process of pubertal mammary development (14). They extend into the mammary fat pad forming a network of branched ducts that occupy most of the mammary fat pad once pubertal development has taken place. To determine if the same hormones responsible for the earliest phase of pubertal mammary development were also responsible for the next phase, ductal morphogenesis, we carried experiments out for a longer period of time. We gave IGF-I + E₂ to IGF-I^(-/-) null animals for 14 days instead of 5 days and found that additional exposure to this combination of hormones resulted in a further increase in the number of TEBs in the mammary gland and also a significant increase the area of the gland occupied by ductal elements (i.e. ductal morphogenesis). However, a significant increase in the number of ducts was not observed. We believe that the numerous ductal buds that were formed along the ducts, as seen in Fig. 4, may be indicative of side branching. It is possible that had we administered IGF-I for periods of more than 14 days we would have observed further branching of ducts. It is also possible that other hormones or growth factors are required for the full process of ductal morphogenesis, especially with regard to the size of the mammary fat pad.

Recent data support a potential role for IGF-I in the adult mammary gland during lactation, in addition to its better established role in early pubertal development. Hadsell et al. (15) and Neuenschwander et al. (16) demonstrated that transgenic animals in which IGF-I was overexpressed during pregnancy and lactation did not undergo expected mammary gland involution after weaning. They ascribed this phenomenon to an effect of IGF-I on inhibiting apoptosis. While these studies do not indicate that IGF-I plays a necessary role in lactation, they support the possibility this might be the case. That GH and IGF-I, along with E₂, may be responsible for the entire process of pubertal ductal morphogenesis raises the possibility that these hormones might have a role in mammary development during later phases including pregnancy, lactation and involution.

In conclusion, our data show that IGF-I is essential for early mammary gland development. They support our previous hypothesis that GH is essential for mammary gland development together with estrogen and that IGF-I fully mediates the action of GH in this process. They further show that longer term exposure to IGF-I causes ductal morphogenesis and may be responsible for the entire process of ductal morphogenesis. That the role of IGF-I in mammary glandular development has now been firmly established places further responsibility upon the scientific community to determine whether inhibition of this growth factor, or its actions, will be as effective in the treatment of breast cancer, as inhibition of estrogen is.

	Footnotes

 
¹ Supported by National Cancer Institute Grant R01-CA64709 and a Merit Review from the Department of Veterans Affairs.

Received April 26, 1999.

	References

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