Abstract
Abstract Increasing evidence indicates that oxidative stress is involved in the progression of estrogen receptor (ER)-positive breast cancer. A moderate increase in cellular oxidants contributes to the genomic instability and to the change in cellular growth pattern, which in turn can facilitate progressive transformation of normal cells into cancer cells. Accordingly, the oxidative stress-related gene expression signature has been suggested to correlate with therapy resistance and poorer outcome in breast cancer. Therefore, it is crucial to determine the antioxidant defense mechanisms that are utilized by breast cancer cells to regulate oxidative stress. Peroxiredoxin 1 (PRDX1) is one of the most prevalent hydrogen peroxide scavenging enzymes in mammalian cells. Our recent studies indicated that PRDX1 is an independent biomarker of favorable prognosis in ER-positive breast cancer. Our results indicate the mechanistic link between PRDX1 and ERα in breast cancer and suggest a role for PRDX1 in mammary carcinogenesis. We provide a molecular explanation for this phenomenon in the current project. To evaluate the importance of PRDX1 activity in ER-positive breast cancer, we have used adenanthin, a newly described PRDX1/2 inhibitor. In our studies, we have shown that adenanthin strongly inhibits metabolism of exogenous hydrogen peroxide by breast cancer cells. This phenomenon is accompanied by a shift from H2O2-degrading PRDX1 dimers into enzymatically inactive monomers and by a dramatic decrease of ERα protein presence in the cells. Moreover, we have observed that incubation of ER-positive breast cancer cells with adenanthin leads to a marked increase in phosphorylation status of proteins associated with Src-Akt-driven signaling in breast cancer. Thus, our results suggest that PRDX1 can play an important role in controlling the switch between estrogen receptor- and growth factor-driven signaling in breast cancer. In summary, in our studies we describe for the first time molecular consequences of rapid dysfunction of PRDX-related system in ER-positive breast cancer. The deeper knowledge on the mechanisms of PRDX1 functioning can change our understanding of the events leading to the progression of ER-positive breast cancer and provide new opportunities for pharmacological interventions in this disease, especially in the context of recent observations connecting the oxidative stress and resistance to endocrine therapy. Citation Format: Malgorzata Bajor, Agata O Zych, Patrick C O'Leary, Anna Czekalska, William M Gallagher, Jakub Golab, Radoslaw Zagozdzon. Adenanthin, a new peroxiredoxin inhibitor, induces a switch between estrogen receptor alpha-mediated and Src/Akt-driven signaling in breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-07-09.
Published Version
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