A 5' distal palindrome within the mouse mammary tumor virus-long terminal repeat recruits a mammary gland-specific complex and is required for a synergistic response to progesterone plus prolactin.

Joseph E. Morabito, Josephine F. Trott, Dorian M. Korz, Heather E. Fairfield, Sarah H. Buck, Russell C. Hovey

Research output: Contribution to journalArticle

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Abstract

Progesterone (P) and prolactin (PRL) fulfill crucial roles during growth and differentiation of the mammary epithelium, and each has been implicated in the pathogenesis of mammary cancer. We previously identified that these hormones synergistically stimulate the proliferation of mouse mammary epithelial cells in vivo, although the mechanism(s) underlying their cooperative effect are unknown. We now report a novel pathway by which P and PRL synergize to activate transcription from the long terminal repeat (LTR) of the mouse mammary tumor virus-LTR (MMTV-LTR) in T47D breast cancer cells. Using serial 5' and 3' deletions of the MMTV-LTR, in addition to selective mutations, we identified that a previously uncharacterized inverted palindrome on the distal enhancer (-941/-930), in addition to a signal transducer and activator of transcription 5 site, was essential for the synergistic activation of transcription by P and PRL. Notably, hormone synergy occurred via a mechanism that was independent of the P receptor DNA-binding elements found in the proximal MMTV-LTR hormone-response element. The palindrome specifically recruited a protein complex (herein termed mammary gland-specific complex) that was almost exclusive to normal and cancerous mammary cells. The synergy between P and PRL occurred via a Janus kinase 2 and c-Src/Fyn-dependent signaling cascade downstream of P and PRL receptors. Combined, our data outline a novel pathway in T47D cells that may facilitate the action(s) of P and PRL during mammary development and breast cancer.

Original languageEnglish (US)
Pages (from-to)75-90
Number of pages16
JournalJournal of Molecular Endocrinology
Volume41
Issue number2
DOIs
StatePublished - Aug 2008
Externally publishedYes

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Mouse mammary tumor virus
Terminal Repeat Sequences
Human Mammary Glands
Prolactin
Progesterone
Breast Neoplasms
Breast
Hormones
STAT5 Transcription Factor
Janus Kinase 2
Prolactin Receptors
Response Elements
Transcriptional Activation
Epithelium
Epithelial Cells
Mutation
Growth
Proteins

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology

Cite this

A 5' distal palindrome within the mouse mammary tumor virus-long terminal repeat recruits a mammary gland-specific complex and is required for a synergistic response to progesterone plus prolactin. / Morabito, Joseph E.; Trott, Josephine F.; Korz, Dorian M.; Fairfield, Heather E.; Buck, Sarah H.; Hovey, Russell C.

In: Journal of Molecular Endocrinology, Vol. 41, No. 2, 08.2008, p. 75-90.

Research output: Contribution to journalArticle

Morabito, Joseph E. ; Trott, Josephine F. ; Korz, Dorian M. ; Fairfield, Heather E. ; Buck, Sarah H. ; Hovey, Russell C. / A 5' distal palindrome within the mouse mammary tumor virus-long terminal repeat recruits a mammary gland-specific complex and is required for a synergistic response to progesterone plus prolactin. In: Journal of Molecular Endocrinology. 2008 ; Vol. 41, No. 2. pp. 75-90.
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abstract = "Progesterone (P) and prolactin (PRL) fulfill crucial roles during growth and differentiation of the mammary epithelium, and each has been implicated in the pathogenesis of mammary cancer. We previously identified that these hormones synergistically stimulate the proliferation of mouse mammary epithelial cells in vivo, although the mechanism(s) underlying their cooperative effect are unknown. We now report a novel pathway by which P and PRL synergize to activate transcription from the long terminal repeat (LTR) of the mouse mammary tumor virus-LTR (MMTV-LTR) in T47D breast cancer cells. Using serial 5' and 3' deletions of the MMTV-LTR, in addition to selective mutations, we identified that a previously uncharacterized inverted palindrome on the distal enhancer (-941/-930), in addition to a signal transducer and activator of transcription 5 site, was essential for the synergistic activation of transcription by P and PRL. Notably, hormone synergy occurred via a mechanism that was independent of the P receptor DNA-binding elements found in the proximal MMTV-LTR hormone-response element. The palindrome specifically recruited a protein complex (herein termed mammary gland-specific complex) that was almost exclusive to normal and cancerous mammary cells. The synergy between P and PRL occurred via a Janus kinase 2 and c-Src/Fyn-dependent signaling cascade downstream of P and PRL receptors. Combined, our data outline a novel pathway in T47D cells that may facilitate the action(s) of P and PRL during mammary development and breast cancer.",
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