Estrogen-activated MDM2 disrupts mammary tissue architecture through a p53-independent pathway
| Autor: | Angelika Brekman, Chong Gao, Nandini Kundu, Gu Xiao, Jill Bargonetti, Jun Yeob Kim |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
p53 Estrogen receptor medicine.disease_cause Retinoblastoma Protein 0302 clinical medicine Phosphorylation Fulvestrant Estradiol Proto-Oncogene Proteins c-mdm2 3. Good health Oncology 030220 oncology & carcinogenesis Gene Knockdown Techniques Female Signal transduction medicine.drug Research Paper estrogen receptor Signal Transduction medicine.medical_specialty Antineoplastic Agents Hormonal medicine.drug_class Mitosis Breast Neoplasms 03 medical and health sciences Breast cancer MDM2 Internal medicine Cell Line Tumor medicine Humans Rb neoplasms Cell Proliferation Cell growth business.industry Estrogens medicine.disease enzymes and coenzymes (carbohydrates) 030104 developmental biology Endocrinology E2F1 Estrogen Cancer research Tumor Suppressor Protein p53 Carcinogenesis business E2F1 Transcription Factor |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Nandini Kundu 1, 2 , Angelika Brekman 1, 3 , Jun Yeob Kim 1 , Gu Xiao 1 , Chong Gao 1, 2 and Jill Bargonetti 1, 2, 3, 4 1 The Department of Biological Sciences Hunter College, City University of New York, New York, NY 10065, USA 2 PhD Program in Biology, The Graduate Center, City University of New York, New York, NY 10016, USA 3 PhD Program in Biochemistry, The Graduate Center, City University of New York, New York, NY 10016, USA 4 Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA Correspondence to: Jill Bargonetti, email: bargonetti@genectr.hunter.cuny.edu Keywords: p53, MDM2, estrogen receptor, Rb, E2F1 Received: September 07, 2016 Accepted: April 29, 2017 Published: May 24, 2017 ABSTRACT The Cancer Genome Atlas (TCGA) data indicate that high MDM2 expression correlates with all subtypes of breast cancer. Overexpression of MDM2 drives breast oncogenesis in the presence of wild-type or mutant p53 (mtp53). Importantly, estrogen-receptor positive (ER+) breast cancers overexpress MDM2 and estrogen mediates this expression. We previously demonstrated that this estrogen-MDM2 axis activates the proliferation of breast cancer cell lines T47D (mtp53 L194F) and MCF7 (wild-type p53) in a manner independent of increased degradation of wild-type p53 (ie, p53-independently). Herein we present data supporting the role of the estrogen-MDM2 axis in regulating cell proliferation and mammary tissue architecture of MCF7 and T47D cells in a p53-independent manner. Inducible shRNA mediated MDM2 knockdown inhibited colony formation in soft agar, decreased mass size and induced lumen formation in matrigel and also significantly reduced mitosis as seen by decreased phospho-histone H3 positive cells. The knockdown of MDM2 in both cell lines decreased Rb phosphorylation and the level of E2F1 protein. This signaling was through the estrogen receptor because fulvestrant (a selective estrogen receptor degrader) decreased MDM2 protein levels and decreased phosphorylation of Rb. Taken together these data indicate that in some ER+ breast cancers the estrogen-MDM2-Rb-E2F1 axis is a central hub for estrogen-mediated p53-independent signal transduction. This is the first indication that estrogen signaling utilizes the estrogen-MDM2 axis to provoke phosphorylation of Rb and increase E2F1 while promoting abnormal mammary architecture. |
| Databáze: | OpenAIRE |
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