OR41-2 ER-coregulatory protein PELP1 overexpression in the mouse mammary gland results in the development of hyperplasia and carcinoma

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR41-Sex Hormone Receptors in Development, Aging and Cancer: Omics Approaches
Basic
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 121 (Moscone Center)
Ratna Vadlamudi*1, Valerie Ann Cortez2, Lewis A Chodosh3 and Rajeshwar Rao Tekmal4
1UTHSCSA, San Antonio, TX, 2UT Health Science Ctr at San Ant, Helotes, TX, 3Univ of PA Sch of Med, West Chester, PA, 4Univ of TX Health Science Center, San Antonio, TX
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. ER coregulator over-expression promotes carcinogenesis and/or progression of endocrine related-cancers where steroid hormones are powerful mitogenic agents. Recent studies in our laboratory as well as others demonstrated that PELP1 is a proto-oncogene and a prognostic indicator of decreased survival in breast cancer patients. PELP1 deregulation in vivo contributes to metastasis and therapy resistance. However, the in vivo significance of PELP1 deregulation during initiation and progression of breast cancer remains unknown. To determine the significance of PELP1 over-expression in mammary tumorigenesis, we generated an inducible, tissue-specific PELP1 expressing transgenic mouse. Transgene induction in adult nulliparous bitransgenic females was achieved with doxycycline administered in their 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 reporter assay. Mammary epithelial-specific expression of PELP1 was validated by immunohistochemistry and Western blot analysis. PELP1-mediated morphological and histological changes were analyzed by examining carmine-stained whole mounts and H&E-stained paraffin embedded mammary glands sections.  We observed an increase in proliferation, extensive side branching and precocious differentiation in PELP1 expressing mammary gland compared to controls. Aged MMTVrtTA-TetOPELP1 bitransgenic mice revealed hyperplasia and preneoplastic changes as early as 12 weeks and mammary tumors occurred at a latency of 10.5 months. Mechanistic studies using tissues from control and PELP1 transgenic mice revealed that PELP1 deregulation modulates expression of a number of known ER target genes and cancer promoting genes. Further PELP1 mediated epigenetic changes via histone modifications play role in PELP1 oncogenic functions in vivo. These results, in our novel animal model, further support that PELP1 deregulation has potential to promote breast tumorigenesis in vivo.

Nothing to Disclose: RV, VAC, LAC, RRT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Studies are supported by Komen grant #KG090447 and NIH F31 award #F31CA165814