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Protein kinase D1 regulates ER α‐positive breast cancer cell growth response to 17β‐estradiol and contributes to poor prognosis in patients
Author(s) -
Karam Manale,
Bièche Ivan,
Legay Christine,
Vacher Sophie,
Auclair Christian,
Ricort JeanMarc
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12322
Subject(s) - antiestrogen , estrogen receptor , gene knockdown , cancer research , tamoxifen , cell growth , breast cancer , estrogen , medicine , estrogen receptor alpha , kinase , endocrinology , biology , cell culture , cancer , microbiology and biotechnology , genetics
About 70% of human breast cancers express and are dependent for growth on estrogen receptor α ( ER α), 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 ( PKD 1) in ER α‐positive breast cancers. Growth of ER α‐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 PKD 1. PKD 1 induces cell growth through both an ER α‐dependent manner, by increasing ER α expression and cell sensitivity to 17β‐estradiol, and an ER α‐independent manner, by reducing cell dependence to estrogens and conferring partial resistance to antiestrogen ICI 182,780. PKD 1 knockdown in MDA ‐ MB ‐415 cells strongly reduced estrogen‐dependent and independent invasion. Quantification of PKD 1 m RNA levels in 38 cancerous and non‐cancerous breast cell lines and in 152 ER α‐positive breast tumours from patients treated with adjuvant tamoxifen showed an association between PKD 1 and ER α expression in 76.3% (29/38) of the breast cell lines tested and a strong correlation between PKD 1 expression and invasiveness ( P  < 0.0001). In tamoxifen‐treated patients, tumours with high PKD 1 m RNA levels ( n  = 77, 50.66%) were significantly associated with less metastasis‐free survival than tumours with low PKD 1 m RNA expression ( n  = 75, 49.34%; P  = 0.031). Moreover, PKD 1 m RNA levels are strongly positively associated with EGFR and vimentin levels ( P  < 0.1). Thus, our study defines PKD 1 as a novel attractive prognostic factor and a potential therapeutic target in breast cancer.

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