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Paraoxonase-2 is upregulated in triple negative breast cancer and contributes to tumor progression and chemoresistance

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Abstract

Triple negative breast cancer (TNBC) displays a high aggressive behavior, tendency to relapse and early metastasize, leading to poor prognosis. The lack of estrogen receptors, and human epidermal growth factor receptor 2, prevents the use of endocrine or molecular targeted therapy, being therapeutical options for TNBC managements mostly limited to surgery, radiotherapy and mainly chemotherapy. While an important number of TNBCs initially responds to chemotherapy, they are prone to develop chemoresistance over the time. Thus, there is an urgent need to identify novel molecular targets to improve the outcome of chemotherapy in TNBC. In this work we focused on the enzyme paraoxonase-2 (PON2) which has been reported to be overexpressed in several tumors contributing to cancer aggressiveness and chemoresistance. Through a case–control study, we analyzed PON2 immunohistochemical expression in breast cancer molecular subtypes Luminal A, Luminal B, Luminal B HER2+, HER2 + and TNBC. Subsequently, we evaluated the in vitro effect of PON2 downregulation on cell proliferation and response to chemotherapeutics. Our results showed that the PON2 expression levels were significantly upregulated in the infiltrating tumors related to the subtypes Luminal A, HER2+ and TNBC compared to the healthy tissue. Furthermore, PON2 downregulation led to a decrease in cell proliferation of breast cancer cells, and significantly enhanced the cytotoxicity of chemotherapeutics on the TNBC cells. Although further analyses are necessary to deeply understand the mechanisms by which the enzyme could participate to breast cancer tumorigenesis, our results seem to demonstrate that PON2 could represent a promising molecular target for TNBC treatment.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

PON2:

Paraoxonase-2

BC:

Breast cancer

TNBC:

Triple negative breast cancer

BRCA:

Breast cancer susceptibility gene

ER:

Estrogen receptors

PR:

Progesterone receptors

HER2:

Human epidermal growth factor receptor 2

pCR:

Pathological complete response

CDDP:

Cisplatin

5-FU:

5-Fluorouracil

PON:

Paraoxonase

PON1:

Paraoxonase-1

PON3:

Paraoxonase-3

DCIS:

Ductal carcinoma in situ

IDC:

Ductal infiltrating carcinoma

ROS:

Reactive oxygen species

FFPE:

Formalin-fixed and paraffin-embedded

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

BCC:

Basal cell carcinoma

UPR:

Unfolded protein response

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Acknowledgements

This work was partially supported by the Fondazione Umberto Veronesi which sponsored Roberto Campagna post-doctoral fellowships in 2021 and 2022.

Funding

This research was partially supported by the Fondazione Umberto Veronesi which sponsored Roberto Campagna post-doctoral fellowships in 2021 and 2022.

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Author notes

  1. Roberto Campagna and Valentina Pozzi contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Sciences, Polytechnic University of Marche, 60100, Ancona, Italy

    Roberto Campagna, Valentina Pozzi, Davide Sartini, Emma Nicol Serritelli & Monica Emanuelli

  2. Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, 60100, Ancona, Italy

    Sara Giorgini, Doriana Morichetti & Gaia Goteri

  3. New York-Marche Structural Biology Center (NY-MaSBiC), Polytechnic University of Marche, 60131, Ancona, Italy

    Monica Emanuelli

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  1. Roberto Campagna
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Contributions

RC: conceptualization, investigation, methodology, formal analysis, writing—original draft preparation. VP: investigation, formal analysis, visualization. SG: investigation, visualization, data curation. DM: investigation, visualization, data curation. GG: supervision, resources. DS: validation, writing—review and editing. ENS: software. ME: supervision, resources, writing—review and editing.

Corresponding author

Correspondence to Davide Sartini.

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The authors declare that they have no conflict of interest.

Ethics approval

This study was performed on formalin fixed and paraffin-embedded tissue specimens, previously collected for diagnostic purposes. According to the Ethics Committee of the Marche region ethical approval for such studies is not required; it is sufficient to send a notification.

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Campagna, R., Pozzi, V., Giorgini, S. et al. Paraoxonase-2 is upregulated in triple negative breast cancer and contributes to tumor progression and chemoresistance. Human Cell 36, 1108–1119 (2023). https://doi.org/10.1007/s13577-023-00892-9

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