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Morabito, Joseph E.

Animal Science

2006

MS

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 of the mouse mammary tumor virus (MMTV-LTR) in T47D breast cancer cells. A previously uncharacterized inverted palindrome on the distal enhancer ( -943/-932) was essential for the synergistic activation of transcription by P and PRL, as was an adjacent STAT5 site.
Notably, hormone synergy occurred in the absence of the proximal MMTV-LTR hormone response region. The palindrome specifically recruits a protein complex (herein termed mammary gland specific complex, MGSC) that is exclusive to normal and cancerous mouse and human mammary cells. Furthermore, both GATA- and STAT-like factors are recruited to the MGSC binding site. The synergy between P and PRL occurs via a Jak2, c-SrclFyn 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.