Abstract
Amplified in breast cancer 1 (AIB1) (also known as steroid receptor coactivator-3) is a nuclear receptor coactivator enhancing estrogen receptor (ER)alpha and progesterone receptor (PR)-dependent transcription in breast cancer. The splice variant AIB1 Delta 3 demonstrates increased ability to promote ER alpha and PR-dependent transcription. Both are implicated in breast cancer risk and antihormone resistance. Conditional transgenic mice tested the in vivo impact of AIB1 Delta 3 overexpression compared with AIB1 on histological features of increased breast cancer risk and growth response to estrogen and progesterone in the mammary gland. Combining expression of either AIB1 or AIB1 Delta 3 with ER alpha overexpression, we investigated in vivo cooperativity. AIB1 and AIB1 Delta 3 overexpression equivalently increased the prevalence of hyperplastic alveolar nodules but not ductal hyperplasia or collagen content. When AIB1 or AIB1 Delta 3 overexpression was combined with ER alpha, both stromal collagen content and ductal hyperplasia prevalence were significantly increased and adenocarcinomas appeared. Overexpression of AIB1 Delta 3, especially combined with overexpressed ER alpha, led to an abnormal response to estrogen and progesterone with significant increases in stromal collagen content and development of a multilayered mammary epithelium. AIB1 Delta 3 overexpression was associated with a significant increase in PR expression and PR downstream signaling genes. AIB1 overexpression produced less marked growth abnormalities and no significant change in PR expression. In summary, AIB1 Delta 3 overexpression was more potent than AIB1 overexpression in increasing stromal collagen content, inducing abnormal mammary epithelial growth, altering PR expression levels, and mediating the response to estrogen and progesterone. Combining ER alpha overexpression with either AIB1 or AIB1 Delta 3 overexpression augmented abnormal growth responses in both epithelial and stromal compartments. (Molecular Endocrinology 25: 549-563, 2011)