Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Human mitochondrial pyrroline-5-carboxylate reductase (PYCR) is a house-keeping enzyme that catalyzes the reduction of Δ1-pyrroline-5-carboxylate to proline. This enzymatic cycle plays pivotal roles in amino acid metabolism, intracellular redox potential and mitochondrial integrity. Here, we hypothesize that <span style="font-style:italic;">PYCR1</span> might be a novel prognostic biomarker and therapeutic target for breast cancer. In this study, breast cancer tissue samples were obtained from Zhejiang University (ZJU set). Immunohistochemistry analysis was performed to detect the protein level of PYCR1, and Kaplan–Meier and Cox proportional analyses were employed in this outcome study. The prognostic significance and performance of <span style="font-style:italic;">PYCR1</span> mRNA were validated on 13 worldwide independent microarray data sets, composed of 2500 assessable breast cancer cases. Our findings revealed that both <span style="font-style:italic;">PYCR1</span> mRNA and protein expression were significantly associated with tumor size, grade and invasive molecular subtypes of breast cancers. Independent and pooled analyses verified that higher <span style="font-style:italic;">PYCR1</span> mRNA levels were significantly associated with poor survival of breast cancer patients, regardless of estrogen receptor (ER) status. For <span style="font-style:italic;">in vitro</span> studies, inhibition of <span style="font-style:italic;">PYCR1</span> by small-hairpin RNA significantly reduced the growth and invasion capabilities of the cells, while enhancing the cytotoxicity of doxorubicin in breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative). Further population study also validated that chemotherapy significantly improved survival in early-stage breast cancer patients with low PYCR1 expression levels. Therefore, <span style="font-style:italic;">PYCR1</span> might serve as a prognostic biomaker for either ER-positive or ER-negative breast cancer subtypes and can also be a potential target for breast cancer therapy.</span>

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