Unique Transcriptomic Changes Underlie Hormonal Interactions During Mammary Histomorphogenesis in Female Pigs

Area of Science:

• Endocrinology and Reproductive Biology
• Molecular Biology and Genomics
• Comparative Mammalian Anatomy

Background:

• Mammary gland (MG) development, crucial for lactation and breast cancer risk, is regulated by ovarian steroids (estrogen [E], progesterone [P]) and prolactin (PRL).
• The pig MG shares significant histomorphogenic similarities with the human breast, making it a valuable model for studying human breast development.

Purpose of the Study:

• To elucidate the transcriptional responses in the pig MG to combinations of E, P, and PRL.
• To correlate transcriptomic changes with phenotypic alterations in the MG, including proliferation and receptor expression.

Main Methods:

• Hormone-ablated pigs were treated with E, a progesterone source, and agents to induce or suppress PRL.
• Phenotypic changes (mitosis, ESR1/PGR levels, pSTAT5, TDLU subtypes) and transcriptomic profiles were analyzed.
• Gene expression data were regressed against MG phenotypes to identify correlations.

Main Results:

• Estrogen significantly altered gene expression, primarily related to mitosis, while PRL influenced fatty acid metabolism and inflammation.
• Estrogen was found to enhance prolactin's action, evidenced by increased pSTAT5 levels.
• 1669 genes correlated with proliferation were identified, with 29 being estrogen-inducible; gene signatures linked to TDLU formation and receptor frequency were also observed.

Conclusions:

• This study links the hormone-regulated genome and phenome of the MG in a human-like complex mammalian model.
• An underexplored synergistic interaction between estrogen and prolactin in MG development is highlighted.