An inducible estrogen receptor co-activator, PELP1 murine breast cancer model

Despite treatment advances, breast cancer remains the second most lethal malignant disease for women worldwide. Although pharmacologic agents that modulate estrogen receptor-alpha (ER) functions or reduce circulating estrogens levels significantly reduced mortality, both de novo and acquired resistance limits efficacy. A critical need for identifying more precise diagnostic/prognostic biomarkers and novel therapeutic targets prompted deeper investigation into ER-coregulatory protein function and regulation. Deregulated PELP1 expression is an independent prognostic biomarker in assessing clinical outcome of luminal-like breast cancer patients. Collectively, several studies suggest PELP1 is an ER coregulator with tumorigenic potential. However, the in vivo significance of PELP1 deregulation during initiation and progression of breast cancer remains unknown. To determine the role of PELP1 over-expression in mammary tumorigenesis, we generated an inducible mammary gland-specific transgenic murine model. pTetOPELP1 mice crossed with mammary gland-specific rtTA mice (MMTVrtTA) to establish two independent MMTVrtTA-TetOPELP1 transgenic lines. Transgene induction was achieved with doxycycline (200mg/mL) administered in drinking water. Concurrent expression and activity of the luciferase gene reporter was detected specifically in the mammary gland by in vivo bioluminescence imaging and luciferase assay. Mammary epithelial-specific expression of PELP1 was validated by immunohistochemistry. PELP1-mediated morphological and histological changes were analyzed by examining carmine-stained whole mounts and H&E-stained sections.  We observed an increase in proliferation, extensive side branching and differentiation, hyperplasia at 3 months and tumors at 12 months. By utilizing the tetracycline-regulatory system, we created a novel, inducible and mammary gland-specific PELP1-expressing transgenic model for future in vivo studies into the molecular mechanism(s) of PELP1-mediated tumorigenesis.