Date of Degree
Laurel A. Eckhardt
James J. Manfredi
Marina K. Holz
Biology | Cancer Biology | Cell and Developmental Biology
Breast cancer, MDM2, p53 independent, Mammary architecture, Estrogen signaling, New York
Estrogen receptor positive (ER+) breast cancers often have MDM2 overexpression indicating a critical role for MDM2 in breast cancer tumorigenesis. The cancer genome atlas (TCGA) found that increased MDM2 expression is one of the four pathways that correlate with all breast cancer subtypes. MDM2 is mainly known as the negative regulator of wild type p53. However, aggressive breast cancers often have MDM2 overexpression and mutant p53 (mtp53). We previously reported that MDM2 provides an estrogen-mediated proliferative advantage to MCF-7 breast cancer cells (ER+, MDM2 overexpression, wild type p53), independent of wild type p53 in both 2D and 3D culture conditions. This and other studies suggest that MDM2 has a p53-independent role in tumorigenesis. To examine the estrogen-induced p53-independent roles of MDM2, we generated T47D breast cancer cells (ER+, MDM2 overexpression, mtp53 L194F) with shRNA to MDM2. As seen previously, estrogen treatment increased MDM2, and MDM2 knockdown did not change p53 protein levels. MDM2 knockdown inhibited estrogen mediated cell proliferation in 2D and 3D anchorage independent soft agar and matrigel culture. MDM2 knockdown decreased mass size, induced lumen formation and significantly reduced the number of phospho-histone H3 positive cells per mass indicating a decrease in mitotic rate. MDM2 knockdown also decreased Rb phosphorylation and E2F1 protein levels. Moreover, blocking estrogen signaling by estrogen antagonist Fulvestrant decreased MDM2 protein levels and phosphorylation of Rb. Our data place MDM2 as a central hub for estrogen-mediated p53-independent signal transduction. We demonstrate that MDM2 provides advantage to estrogen-induced breast cancer cell proliferation and disruption of mammary architecture through ER-MDM2-phosphoRb-E2F1 signaling pathway.
Kundu, Nandini, "The P53 Independent Functions of Estrogen-Activated MDM2 in Cell Signaling and Mammary Architecture" (2017). CUNY Academic Works.