A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17β-estradiol: ERα signaling and cell proliferation in breast cancer cells. (15th January 2018)

• Record Type: Journal Article
• Authors: Busonero, Claudia; Leone, Stefano; Klemm, Cinzia; Acconcia, Filippo
• Is Part Of: Molecular and cellular endocrinology. Volume 460(2018)
• Page Start: 229
• Page End: 237
• Publication Date: 2018-01-15
• Subjects: 17β-estradiol -- Estrogen receptor -- Breast cancer -- Drug screening -- Carfilzomib; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2017.07.027
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Most cases of breast cancer (BC) are estrogen receptor α-positive (ERα+) at diagnosis. The presence of ERα drives the therapeutic approach for this disease, which often consists of endocrine therapy (ET). 4OH-Tamoxifen and faslodex ( i.e., fulvestrant - ICI182, 780) are two ETs that render tumor cells insensitive to 17β-estradiol (E2)-dependent proliferative stimuli and prevent BC progression. However, ET has limitations and serious failures in different tissues and organs. Thus, there is an urgent need to identify novel drugs to fight BC in the clinic. Re-positioning of old drugs for new clinical purposes is an attractive alternative for drug discovery. For this analysis, we focused on the modulation of intracellular ERα levels in BC cells as target for the screening of about 900 Food and Drug Administration (FDA) approved compounds that would hinder E2:ERα signaling and inhibit BC cell proliferation. We found that carfilzomib induces ERα degradation and prevents E2 signaling and cell proliferation in two ERα+ BC cell lines. Remarkably, the analysis of carfilzomib effects on a cell model system with an acquired resistance to 4OH-tamoxifen revealed that this drug has an antiproliferative effect superior to faslodex in BC cells. Therefore, our results identify carfilzomib as a drug preventing E2:ERα signaling and cell proliferation in BC cells and suggest its possible re-position for the treatment of ERα+ BC as well as for those diseases that have acquired resistance to 4OH-tamoxifen. Highlights: Novel anti-breast cancer drugs can be identified by evaluating the modulation of ERα intracellular levels. Carfilzomib induces ERα degradation in breast cancer cells. Carfilzomib prevents E2:ERα signaling in breast cancer cells. Carfilzomib could be re-positioned for treating breast cancers including those resistant to 4OH-tamoxifen.