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.
Highlights
A majority of breast cancers are estrogen–receptor alpha positive (ER+) and many of these are resistant to therapies targeting their hormone receptor status [1]
To determine if estrogen signaling for tumorigenic properties requires the p53-independent MDM2 pathway we evaluated the effect of MDM2 knockdown on estrogen driven MCF7 and T47D proliferation in soft agar
Estrogen treatment increases the p53-independent MDM2 signaling in T47D cell lines and in MCF7 cells with wild-type p53 [10, 11]
Summary
A majority of breast cancers are estrogen–receptor alpha positive (ER+) and many of these are resistant to therapies targeting their hormone receptor status [1]. Many ER+ breast cancers have MDM2 overexpression suggesting that MDM2 is an ER+ axis driver oncogene that can be targeted for cancer therapy [2,3,4]. The mdm gene contains a single nucleotide polymorphism, SNP 309, where T is changed to G thereby further increasing estrogen activated MDM2 expression by increased recruitment of the Sp1 transcription factor to the promoter region of the gene [9, 12]. This mdm SNP309 G allele accelerates tumor formation in a gender specific and hormone dependent manner [9]. We investigate the estrogenMDM2 axis as a pathway that functions in some ER+ cells to promote p53-independent tumorigenic outcomes
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