Protein Kinase D1 (PKD1) Is a New Functional Non-Genomic Target of Bisphenol A in Breast Cancer Cells

Messaouda Merzoug-Larabi,Christine Legay,Sophie Lognon,Sylvie Babajko,Sophia Loiodice,Ilige Youssef,Ai Thu Bui,Jean-Marc Ricort

doi:10.3389/fphar.2019.01683

Abstract

Exposure to bisphenol A (BPA), one of the most widespread endocrine disruptors present in our environment, has been associated with the recent increased prevalence and severity of several diseases such as diabetes, obesity, autism, reproductive and neurological defects, oral diseases, and cancers such as breast tumors. BPA is suspected to act through genomic and non-genomic pathways. However, its precise molecular mechanisms are still largely unknown. Our goal was to identify and characterize a new molecular target of BPA in breast cancer cells in order to better understand how this compound may affect breast tumor growth and development. By using in vitro (MCF-7, T47D, Hs578t, and MDA-MB231 cell lines) and in vivo models, we demonstrated that PKD1 is a functional non-genomic target of BPA. PKD1 specifically mediates BPA-induced cell proliferation, clonogenicity, and anchorage-independent growth of breast tumor cells. Additionally, low-doses of BPA (≤10− 8 M) induced the phosphorylation of PKD1, a key signature of its activation state. Moreover, PKD1 overexpression increased the growth of BPA-exposed breast tumor xenografts in vivo in athymic female Swiss nude (Foxn1nu/nu) mice. These findings further our understanding of the molecular mechanisms of BPA. By defining PKD1 as a functional target of BPA in breast cancer cell proliferation and tumor development, they provide new insights into the pathogenesis related to the exposure to BPA and other endocrine disruptors acting similarly.

Highlights

According to the World Health Organization’s definition (2002), endocrine disruptors are chemical compounds that can interfere with the endocrine system and cause deleterious health effects to organisms or even their descendants
We have identified the serine/threonine kinase PKD1 as a new non-genomic functional target of bisphenol A (BPA) in breast cancer cells in vitro
We showed that increasing PKD1 expression levels significantly sensitized breast cancer cells to BPA-induced in vivo tumor growth

Summary

Introduction

According to the World Health Organization’s definition (2002), endocrine disruptors are chemical compounds that can interfere with the endocrine system and cause deleterious health effects to organisms or even their descendants. Exposure to BPA has been associated with the recent increased incidence of prostate and breast cancer (reviewed in Seachrist et al, 2016). Gestational or perinatal exposure of rodents and monkeys to BPA alters mammary gland development, increasing the risk of later onset of breast tumors (Munoz-de-Toro et al, 2005; Tharp et al, 2012; Mandrup et al, 2016). BPA serum concentrations positively correlate with higher breast density, a well-known risk factor for the subsequent development of breast tumors (Sprague et al, 2013). Exposure to BPA increases the number of pre-cancerous mammary lesions and breast carcinomas and promotes metastasis (Murray et al, 2007; Jenkins et al, 2011)

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