title: Protein kinase D1 regulates ERα-positive breast cancer cell growth response to 17β-estradiol and contributes to poor prognosis in patients.
abstract: About 70% of human breast cancers express and are dependent for growth on estrogen receptor α (ERα), and therefore are sensitive to antiestrogen therapies. However, progression to an advanced, more aggressive phenotype is associated with acquisition of resistance to antiestrogens and/or invasive potential. In this study, we highlight the role of the serine/threonine-protein kinase D1 (PKD1) in ERα-positive breast cancers. Growth of ERα-positive MCF-7 and MDA-MB-415 human breast cancer cells was assayed in adherent or anchorage-independent conditions in cells overexpressing or depleted for PKD1. PKD1 induces cell growth through both an ERα-dependent manner, by increasing ERα expression and cell sensitivity to 17β-estradiol, and an ERα-independent manner, by reducing cell dependence to estrogens and conferring partial resistance to antiestrogen ICI 182,780. PKD1 knockdown in MDA-MB-415 cells strongly reduced estrogen-dependent and independent invasion. Quantification of PKD1 mRNA levels in 38 cancerous and non-cancerous breast cell lines and in 152 ERα-positive breast tumours from patients treated with adjuvant tamoxifen showed an association between PKD1 and ERα expression in 76.3% (29/38) of the breast cell lines tested and a strong correlation between PKD1 expression and invasiveness (P < 0.0001). In tamoxifen-treated patients, tumours with high PKD1 mRNA levels (n = 77, 50.66%) were significantly associated with less metastasis-free survival than tumours with low PKD1 mRNA expression (n = 75, 49.34%; P = 0.031). Moreover, PKD1 mRNA levels are strongly positively associated with EGFR and vimentin levels (P < 0.0000001). Thus, our study defines PKD1 as a novel attractive prognostic factor and a potential therapeutic target in breast cancer.
authors.affiliation: Laboratoire de Biologie et de Pharmacologie Appliquée, UMR 8113 CNRS, Ecole Normale Supérieure de Cachan, Cachan, France.
authors.forename: Manale
authors.initials: M
authors.lastname: Karam
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Christine
authors.initials: C
authors.lastname: Legay
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.forename: Christian
authors.initials: C
authors.lastname: Auclair
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ricort
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D011379:Prognosis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use; D014746:Vimentin / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D004958:Estradiol; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D000077267:Fulvestrant; D050396:TRPP Cation Channels; D013629:Tamoxifen; D014746:Vimentin; C506487:ESR1 protein, human
keywords: antiestrogen therapy; breast cancer; estrogen receptor α; invasion; proliferation; protein kinase D1