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Prolactin/androgen-inducible carboxypeptidase-D increases with nitrotyrosine and Ki67 for breast cancer progression in vivo, and upregulates progression markers VEGF-C and Runx2 in vitro

  • Preclinical study
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Abstract

Purpose

Carboxypeptidase-D (CPD) cleaves C-terminal arginine (Arg) to produce nitric oxide (NO). Upregulation of CPD and NO by 17β-estradiol, prolactin (PRL), and androgen increases survival of human breast cancer (BCa) cells in vitro. To demonstrate similar events in vivo, CPD, nitrotyrosine (NT, hallmark of NO action), androgen receptor (AR), prolactin receptor (PRLR), and phospho-Stat5a (for activated PRLR) levels were evaluated in benign and malignant human breast tissues, and correlated with cell proliferation (Ki67) and BCa progression (Cullin-3) biomarkers.

Methods

Paraffin-embedded breast tissues were analyzed by immunohistochemistry (IHC). BCa progression markers in human MCF-7 and T47D BCa cell lines treated with NO donor SIN-1 or PRL, ±CPD inhibitors were analyzed by RT-qPCR and immunoblotting.

Results

IHC showed progressive increases in CPD, NT, Ki67, and Cullin-3 from low levels in benign tissues to high levels in ductal carcinoma in situ, low-grade, high-grade, and triple-negative BCa. CPD and NT staining were closely associated, implicating CPD in NO production. Phospho-Stat5a increased significantly from benign to high-grade BCa and was mostly nuclear. AR and PRLR were abundant in benign breast and BCa, including triple-negative tumors. SIN-1 and PRL increased VEGF-C and Runx2, but not Cullin-3, in BCa cell lines. PRL induction of VEGF-C and Runx2 was inhibited partly by CPD inhibitors, implicating NO, produced by PRL-regulated CPD, in BCa progression.

Conclusions

The CPD-Arg-NO pathway contributes to BCa progression in vitro and in vivo. PRL/androgen activation of the pathway support combined AR and PRLR blockade as an additional therapy for BCa.

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Acknowledgements

This study was funded by the Breast Cancer Society of Canada/QEII Foundation/Beatrice Hunter Cancer Research Institute for Breast Cancer Research (to CKLT and PJB) and Canadian Breast Cancer Foundation (CBCF)/Atlantic (to CKLT). ERC received a summer studentship from CBCF/Atlantic.

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Authors and Affiliations

  1. Departments of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada

    Lynn N. Thomas, Emily R. Chedrawe & Catherine K. L. Too

  2. Pathology and Laboratory Medicine, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada

    Penelope J. Barnes

  3. Department of Biochemistry & Molecular Biology, Sir Charles Tupper Medical Building, 5850 College Street, P.O. Box 15000, Halifax, NS, B3H 4R2, Canada

    Catherine K. L. Too

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  1. Lynn N. Thomas
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Correspondence to Catherine K. L. Too.

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Thomas, L.N., Chedrawe, E.R., Barnes, P.J. et al. Prolactin/androgen-inducible carboxypeptidase-D increases with nitrotyrosine and Ki67 for breast cancer progression in vivo, and upregulates progression markers VEGF-C and Runx2 in vitro. Breast Cancer Res Treat 164, 27–40 (2017). https://doi.org/10.1007/s10549-017-4223-7

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