Ubiquitin‐activating enzyme is necessary for 17β‐estradiol‐induced breast cancer cell proliferation and migration

Abstract

The sex steroid hormone 17b-estradiol (E2) regulates breast cancer (BC) cell proliferation and migration through the activation of a plethora of signal transduction cascades (e.g., PI3K/ AKT activation) starting after E2 binding to the estrogen receptor alpha (ERa). The activity of the ubiquitin (Ub)-system modulates many physiological processes (e.g., cell proliferation and migration), and recently, a specific inhibitor (Pyr-41) of the Ub-activating enzyme (E 1 ), which works as the activator of the Ub-based signaling, has been identified to prevent the functions of the Ub-system. Here, by using Pyr-41, we studied the involvement of the Ub-system in E2-induced signaling to proliferation and migration of BC cells. Our data indicate that E 1 activity is involved in the E2:ERa signaling important for cell proliferation and migration through the modulation of the E2-evoked activation of the PI3K/AKT and the p38/MAPK pathways. These discoveries indicate a new molecular circuitry that can be further explored to define new opportunities for BC treatment. V C 2014 IUBMB Life, 66(8):578-585, 2014

Obesity as potential breast cancer risk factor for postmenopausal women

“… 34 , 35 E2-activated ER controls carcinogenesis of breast by using intricate signaling pathways that manages multiple cellular responsibilities, namely angiogenesis, migration, growth and apoptosis. 36 , 37 , 38 ER is principally a protein which acts like a ligand dependent transcription factor. Usually, the E2/ER complexes after fusion and co-regulator enlistment, bind easily to estrogen responding space in the promoter area of targeted genes.…”

A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17β-estradiol: ERα signaling and cell proliferation in breast cancer cells

“…As E2-dependent transcription of cyclin D1 is necessary for hormone-dependent induction of cell cycle progression [15,[27][28][29], the ability of E2 to induce cellular proliferation in MCF-7 and ZR-75-1 cells was further evaluated in the presence of carfilzomib. As expected, cell cycle analysis revealed that ICI and carfilzomib administration to MCF-7 and ZR-75-1 cells prevents E2-triggered 1 0 cell cycle progression.…”

Modulation of 17β‐Estradiol Signaling on Cellular Proliferation by Caveolin‐2

“…As E2‐dependent transcription of both cyclin D1 and Bcl‐2 contributes to the E2‐dependent induction of cell cycle progression (Castoria et al, ; Marino et al, ; Acconcia et al, ; Pesiri et al, ), the ability of E2 to induce cellular proliferation in MCF‐7 cells in which either caveolin‐2 or caveolin‐1 expression was reduced was then evaluated. As expected, E2 treatment increased the number of MCF‐7 control cells but not that of MCF‐7 caveolin‐2‐ and caveolin‐1‐KD cells (Fig.…”

“…It has been previously demonstrated that the regulation of ERα content in different breast cancer cell lines is under the control of E2‐induced extra‐nuclear signaling (i.e., PI3K/AKT activation) (La Rosa et al, ; Pesiri et al, ; Totta et al, , ). Thus, the ability of E2 to activate ERα extra‐nuclear signaling in caveolin‐2‐ or caveolin‐1‐depleted MCF‐7 cells was tested.…”