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ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation.

Jones FE, Welte T, Fu XY, Stern DF - J. Cell Biol. (1999)

Bottom Line: However, whey acidic protein mRNA was reduced, and alpha-lactalbumin mRNA was undetectable.This phosphorylation required an intact Stat5 SH2 domain.In summary, our results demonstrate that ErbB4 signaling is necessary for mammary terminal differentiation and Stat5 activation at mid-lactation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, BML 342, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.

ABSTRACT
Signaling by members of the epidermal growth factor receptor family plays an important role in breast development and breast cancer. Earlier work suggested that one of these receptors, ErbB4, is coupled to unique responses in this tissue. To determine the function of ErbB4 signaling in the normal mouse mammary gland, we inactivated ErbB4 signaling by expressing a COOH terminally deleted dominant-negative allele of ErbB4 (ErbB4DeltaIC) as a transgene in the mammary gland. Despite the expression of ErbB4DeltaIC from puberty through later stages of mammary development, an ErbB4DeltaIC-specific phenotype was not observed until mid-lactation. At 12-d postpartum, lobuloalveoli expressing ErbB4DeltaIC protein were condensed and lacked normal lumenal lactation products. In these lobuloalveoli, beta-casein mRNA, detected by in situ hybridization, was normal. However, whey acidic protein mRNA was reduced, and alpha-lactalbumin mRNA was undetectable. Stat5 expression was detected by immunohistochemistry in ErbB4DeltaIC-expressing tissue. However, Stat5 was not phosphorylated at Y694 and was, therefore, probably inactive. When expressed transiently in 293T cells, ErbB4 induced phosphorylation of Stat5. This phosphorylation required an intact Stat5 SH2 domain. In summary, our results demonstrate that ErbB4 signaling is necessary for mammary terminal differentiation and Stat5 activation at mid-lactation.

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Immunohistochem- ical detection of Stat5 protein in ErbB4ΔIC-expressing mammary glands at 12-d postpartum. High magnification photomicrographs of expanded lobuloalveoli lacking detectable ErbB4ΔIC expression (A–C) or a different region of the same section containing condensed lobuloalveoli expressing high levels of ErbB4ΔIC protein (D–F). Sections were stained with hematoxylin/eosin (A and D), or stained by immunohistochemistry with rabbit serum negative control (B and E) or rabbit anti-Stat5 (C and F). Bar in D, 30 μm.
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Figure 4: Immunohistochem- ical detection of Stat5 protein in ErbB4ΔIC-expressing mammary glands at 12-d postpartum. High magnification photomicrographs of expanded lobuloalveoli lacking detectable ErbB4ΔIC expression (A–C) or a different region of the same section containing condensed lobuloalveoli expressing high levels of ErbB4ΔIC protein (D–F). Sections were stained with hematoxylin/eosin (A and D), or stained by immunohistochemistry with rabbit serum negative control (B and E) or rabbit anti-Stat5 (C and F). Bar in D, 30 μm.

Mentions: The condensed lobuloalveoli and pattern of impaired milk gene expression observed in ErbB4ΔIC-expressing mammary tissue resembles mammary defects observed in mice with Stat5 gene disruptions (Liu et al. 1996b; Teglund et al. 1998). Stat5 expression was determined by immunohistochemistry in sections of mammary glands at 12-d postpartum, containing both normal (Fig. 4 A) and ErbB4ΔIC-expressing lobuloalveoli (Fig. 4 D). Strong immunostaining was detected in the nuclei of both normal (compare Fig. 4B and Fig. C) and ErbB4ΔIC-expressing lobuloalveoli (compare Fig. 4E and Fig. F).


ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation.

Jones FE, Welte T, Fu XY, Stern DF - J. Cell Biol. (1999)

Immunohistochem- ical detection of Stat5 protein in ErbB4ΔIC-expressing mammary glands at 12-d postpartum. High magnification photomicrographs of expanded lobuloalveoli lacking detectable ErbB4ΔIC expression (A–C) or a different region of the same section containing condensed lobuloalveoli expressing high levels of ErbB4ΔIC protein (D–F). Sections were stained with hematoxylin/eosin (A and D), or stained by immunohistochemistry with rabbit serum negative control (B and E) or rabbit anti-Stat5 (C and F). Bar in D, 30 μm.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2164978&req=5

Figure 4: Immunohistochem- ical detection of Stat5 protein in ErbB4ΔIC-expressing mammary glands at 12-d postpartum. High magnification photomicrographs of expanded lobuloalveoli lacking detectable ErbB4ΔIC expression (A–C) or a different region of the same section containing condensed lobuloalveoli expressing high levels of ErbB4ΔIC protein (D–F). Sections were stained with hematoxylin/eosin (A and D), or stained by immunohistochemistry with rabbit serum negative control (B and E) or rabbit anti-Stat5 (C and F). Bar in D, 30 μm.
Mentions: The condensed lobuloalveoli and pattern of impaired milk gene expression observed in ErbB4ΔIC-expressing mammary tissue resembles mammary defects observed in mice with Stat5 gene disruptions (Liu et al. 1996b; Teglund et al. 1998). Stat5 expression was determined by immunohistochemistry in sections of mammary glands at 12-d postpartum, containing both normal (Fig. 4 A) and ErbB4ΔIC-expressing lobuloalveoli (Fig. 4 D). Strong immunostaining was detected in the nuclei of both normal (compare Fig. 4B and Fig. C) and ErbB4ΔIC-expressing lobuloalveoli (compare Fig. 4E and Fig. F).

Bottom Line: However, whey acidic protein mRNA was reduced, and alpha-lactalbumin mRNA was undetectable.This phosphorylation required an intact Stat5 SH2 domain.In summary, our results demonstrate that ErbB4 signaling is necessary for mammary terminal differentiation and Stat5 activation at mid-lactation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, BML 342, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.

ABSTRACT
Signaling by members of the epidermal growth factor receptor family plays an important role in breast development and breast cancer. Earlier work suggested that one of these receptors, ErbB4, is coupled to unique responses in this tissue. To determine the function of ErbB4 signaling in the normal mouse mammary gland, we inactivated ErbB4 signaling by expressing a COOH terminally deleted dominant-negative allele of ErbB4 (ErbB4DeltaIC) as a transgene in the mammary gland. Despite the expression of ErbB4DeltaIC from puberty through later stages of mammary development, an ErbB4DeltaIC-specific phenotype was not observed until mid-lactation. At 12-d postpartum, lobuloalveoli expressing ErbB4DeltaIC protein were condensed and lacked normal lumenal lactation products. In these lobuloalveoli, beta-casein mRNA, detected by in situ hybridization, was normal. However, whey acidic protein mRNA was reduced, and alpha-lactalbumin mRNA was undetectable. Stat5 expression was detected by immunohistochemistry in ErbB4DeltaIC-expressing tissue. However, Stat5 was not phosphorylated at Y694 and was, therefore, probably inactive. When expressed transiently in 293T cells, ErbB4 induced phosphorylation of Stat5. This phosphorylation required an intact Stat5 SH2 domain. In summary, our results demonstrate that ErbB4 signaling is necessary for mammary terminal differentiation and Stat5 activation at mid-lactation.

Show MeSH
Related in: MedlinePlus