PKD1 is a potential biomarker and therapeutic target in triple-negative breast cancer.

Caroline Spasojevic,Martine Humbert,Christian Auclair,Franck Assayag,Ivan Bièche,Elisabetta Marangoni,Sophie Château-Joubert,Manale Karam,Sophie Vacher,Didier Meseure,Jean Marc Ricort,Marie Regairaz

doi:10.18632/oncotarget.25292

Abstract

Protein Kinase D1 (PKD1) is a serine/threonine kinase encoded by the PRKD1 gene. PKD1 has been previously shown to be a prognostic factor in ERα+ tamoxifen-resistant breast tumors and PKD1 overexpression confers estrogen independence to ERα+ MCF7 cells. In the present study, our goal was to determine whether PKD1 is a prognostic factor and/or a relevant therapeutic target in breast cancer. We analyzed PRKD1 mRNA levels in 527 primary breast tumors. We found that high PRKD1 mRNA levels were significantly and independently associated with a low metastasis-free survival in the whole breast cancer population and in the triple-negative breast cancer (TNBC) subtype specifically. High PRKD1 mRNA levels were also associated with a low overall survival in TNBC. We identified novel PKD1 inhibitors and assessed their antitumor activity in vitro in TNBC cell lines and in vivo in a TNBC patient-derived xenograft (PDX) model. Pharmacological inhibition and siRNA-mediated depletion of PKD1 reduced colony formation in MDA-MB-436 TNBC cells. PKD1 inhibition also reduced tumor growth in vivo in a TNBC PDX model. Together, these results establish PKD1 as a poor prognostic factor and a potential therapeutic target in TNBC.

Highlights

Breast cancer is currently the first cause of death from cancer in women, and the second most common cancer overall, with 1.7 million new cases and 521,900 deaths each year according to the most recent worldwide study [1]
To determine whether the expression of PKD family members is associated with prognosis in breast cancer, we first analyzed PRKD1, PRKD2 and PRKD3 mRNA levels by quantitative RT-PCR in a large series of 527 primary breast tumors with known clinical/pathological status and long-term outcome (Figure 1A)
PRKD1 mRNA expression was detected in 99.8% of cases while PRKD2 and PRKD3 mRNA expressions were detected in all cases

Summary

Introduction

Breast cancer is currently the first cause of death from cancer in women, and the second most common cancer overall, with 1.7 million new cases and 521,900 deaths each year according to the most recent worldwide study [1]. Breast cancer prognosis is variable, depending mostly on tumor stage at diagnosis and on the molecular features of the tumor. Breast tumors can be divided into different molecular subtypes: i) the Luminal A and B subtypes, expressing high levels of estrogen and/ or progesterone receptors, ii) the HER2+ subtype, overexpressing the human epidermal growth factor receptor 2 (HER2) protein and iii) the triple-negative breast cancers (TNBC), expressing none of the hormone receptors and showing no HER2 amplification and/or overexpression [2, 3]. The poor prognosis of TNBC results from the lack of treatment options for these patients, who cannot benefit from either hormone or HER2-targeted therapies [4]. It remains very important to identify new targets and associated biomarkers for breast cancer therapy

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