oa Protein Kinase D1 Regulates Erα-positive Breast Cancer Cell Growth Response To 17β­estradiol And Contributes To Poor Prognosis In Patients

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 the present 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 17β­estradiol, 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 tumors 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, tumors with high PKD1 mRNA levels (n=77, 50.66%) were significantly associated with less metastasis-free survival than tumors 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.