Prox1 Suppresses the Proliferation of Breast Cancer Cells via Direct Inhibition of c-Myc Gene Expression

Sep 24, 2026

Breast cancer is among the most lethal malignancies in women worldwide, marked by rapid growth and low survival despite therapy advances. Prox1 is identified as a negative regulator of proliferation and tumor-related metabolism in breast cancer. Patient tumors show reduced Prox1, while higher Prox1 correlates with better prognosis. Prox1 suppresses proliferation, migration, and the Warburg effect without inducing apoptosis, and inhibits tumor growth in vivo in xenograft models. Mechanistically, Prox1 directly represses c-Myc transcription and downstream targets, reversing effects when c-Myc is overexpressed.

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CategoryHealthcare

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Abstract

Introduction

cells Article Prox1 Suppresses the Proliferation of Breast Cancer Cells via Direct Inhibition of c-Myc Gene Expression Artemis Michail 1,2, Dimitrios Gkikas 1, Dimitris Stellas 3, Valeria Kaltezioti 1 and Panagiotis K. Politis 1,4, * Citation: Michail, A.; Gkikas, D.; Stellas, D.; Kaltezioti, V.; Politis, P.K. Prox1 Suppresses the Proliferation of Breast Cancer Cells via Direct Inhibition of c-Myc Gene Expression. Cells 2023, 12, 1869. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/cells12141869](10.3390/cells12141869) Academic Editors: Marilena V. Iorio and Tiziana Triulzi Received: 27 June 2023 Revised: 13 July 2023 Accepted: 13 July 2023 Published: 17 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str., 115 27 Athens, Greece; [artemisbio@gmail.com](artemisbio@gmail.com) (A.M.); [dgkikas@bioacademy.gr](dgkikas@bioacademy.gr) (D.G.); [vkaltezioti@bioacademy.gr](vkaltezioti@bioacademy.gr) (V.K.) 2 Department of Biology, University of Patras, 265 04 Patras, Greece 3 Institute of Chemical Biology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 116 35 Athens, Greece; [dstellas@eie.gr](dstellas@eie.gr) 4 School of Medicine, European University Cyprus, Nicosia 2404, Cyprus * [Correspondence: ppolitis@bioacademy.gr](Correspondence: ppolitis@bioacademy.gr) Abstract: Breast cancer is one of the most lethal malignancies in women worldwide and is characterized by rapid growth and low survival rates, despite advances in tumor biology and therapies. Novel therapeutic approaches require new insights into the molecular mechanisms of malignant transformation and progression. To this end, here, we identiﬁed Prox1 as a negative regulator of proliferation and tumor-related metabolism in breast cancer. In particular, we showed that breast tumors from human patients exhibited reduced levels of Prox1 expression, while high expression levels of Prox1 were associated with a favorable prognosis in breast cancer patients. Moreover, we experimentally demonstrated that Prox1 was sufﬁcient to strongly suppress proliferation, migration, and the Warburg effect in human breast cancer cells without inducing apoptosis. Most importantly, over-expression of Prox1 inhibited breast tumor growth in vivo in both heterotopic and orthotopic xenograft mouse models. The anti-tumorigenic effect of Prox1 was mediated by the direct repression of c-Myc transcription and its downstream target genes. Consistently, c-Myc over-expression from anartiﬁcial promoter that was not targeted by Prox1 reversed Prox1's anti-tumor effects. These ﬁndings suggest that Prox1 has a tumor suppressive role via direct transcriptional regulation of c-Myc, making it a promising therapeutic gene for breast cancer. Keywords: metabolism; gene regulation; Warburg effect; PDK1; MPC1 1. Introduction Prox1 is a vertebrate homeobox transcription regulator that plays an important role in embryonic development. Mouse embryos lacking Prox1 die early in embryogenesis at E14.5 [1] . Prox1 is a regulatory factor in lymphatic, liver, pancreas, heart, lens, retina, and nervous system development [1–10] . Furthermore, Prox1 has been implicated ina large number of human cancers, including blood, pancreatic, liver, colon, lung, and nervous system-related tumors, displaying both suppressing and oncogenic roles in atissue dependent manner [11–23] . It has also been previously shown that Prox1 expression is repressed in breast cancer cells due to epigenetic silencing [24] . Consistently, a recently reported Genome-Wide A

FAQs

What role does Prox1 play in breast cancer progression?

Prox1 acts as a negative regulator of proliferation and tumor-related metabolism. It is associated with better prognosis and suppresses key cancer behaviors.

How does Prox1 affect tumor metabolism and cell behavior?

Prox1 suppresses proliferation and migration and inhibits the Warburg effect in human breast cancer cells. It does so without inducing apoptosis.

How is the anti-tumor effect of Prox1 mediated?

The anti-tumor activity is mediated by direct repression of c-Myc transcription and downstream target genes. Restoring c-Myc expression reverses Prox1’s effects.

Sep 24, 2026

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