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

Artemis Michail; Dimitrios Gkikas; Dimitris Stellas; Valeria Kaltezioti; Panagiotis K Politis

doi:10.3390/cells12141869

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

Cells. 2023 Jul 17;12(14):1869. doi: 10.3390/cells12141869.

Authors

Artemis Michail^{1

2}, Dimitrios Gkikas¹, Dimitris Stellas³, Valeria Kaltezioti¹, Panagiotis K Politis^{1

4}

Affiliations

¹ Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Efesiou Str., 115 27 Athens, Greece.
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.
⁴ School of Medicine, European University Cyprus, Nicosia 2404, Cyprus.

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 an artificial 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: MPC1; PDK1; Warburg effect; gene regulation; metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Cell Proliferation
Female
Gene Expression
Homeodomain Proteins* / genetics
Homeodomain Proteins* / metabolism
Humans
Mice
Transcription Factors / genetics
Tumor Suppressor Proteins / metabolism

Substances

Homeodomain Proteins
Tumor Suppressor Proteins
Transcription Factors

Grants and funding

This work was supported by Fondation Sante grant (Politis-round2017) and the Hellenic Foundation for Research and Innovation (H.F.R.I) under the “First Call for H.F.R.I Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 1782) to P.K.P. This research was also co-financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH-CREATE-INNOVATE (Project Number: T2EDK-02075).