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Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.

Publication ,  Journal Article
Chen, C-C; Stairs, DB; Boxer, RB; Belka, GK; Horseman, ND; Alvarez, JV; Chodosh, LA
Published in: Genes Dev
October 1, 2012

Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.

Duke Scholars

Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

October 1, 2012

Volume

26

Issue

19

Start / End Page

2154 / 2168

Location

United States

Related Subject Headings

  • STAT5 Transcription Factor
  • Proto-Oncogene Proteins c-akt
  • Prolactin
  • Pregnancy
  • PTEN Phosphohydrolase
  • Milk Proteins
  • Mice
  • Mammary Glands, Animal
  • Lactation
  • Gene Expression Regulation
 

Citation

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MLA
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Chen, C.-C., Stairs, D. B., Boxer, R. B., Belka, G. K., Horseman, N. D., Alvarez, J. V., & Chodosh, L. A. (2012). Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev, 26(19), 2154–2168. https://doi.org/10.1101/gad.197343.112
Chen, Chien-Chung, Douglas B. Stairs, Robert B. Boxer, George K. Belka, Nelson D. Horseman, James V. Alvarez, and Lewis A. Chodosh. “Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.Genes Dev 26, no. 19 (October 1, 2012): 2154–68. https://doi.org/10.1101/gad.197343.112.
Chen C-C, Stairs DB, Boxer RB, Belka GK, Horseman ND, Alvarez JV, et al. Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev. 2012 Oct 1;26(19):2154–68.
Chen, Chien-Chung, et al. “Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.Genes Dev, vol. 26, no. 19, Oct. 2012, pp. 2154–68. Pubmed, doi:10.1101/gad.197343.112.
Chen C-C, Stairs DB, Boxer RB, Belka GK, Horseman ND, Alvarez JV, Chodosh LA. Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev. 2012 Oct 1;26(19):2154–2168.

Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

October 1, 2012

Volume

26

Issue

19

Start / End Page

2154 / 2168

Location

United States

Related Subject Headings

  • STAT5 Transcription Factor
  • Proto-Oncogene Proteins c-akt
  • Prolactin
  • Pregnancy
  • PTEN Phosphohydrolase
  • Milk Proteins
  • Mice
  • Mammary Glands, Animal
  • Lactation
  • Gene Expression Regulation