Src Mediates Prolactin-Dependent Proliferation of T47D and MCF7 Cells via the Activation of Focal Adhesion Kinase/Erk1/2 and Phosphatidylinositol 3-Kinase Pathways

Acosta, Juan J.; Muñoz, Riansares; González, Lorena; Subtil‐Rodríguez, Alicia; Domínguez-Cáceres, María Aurora; García-Martínez, José Manuel; Calcabrini, Annarica; Lazaro-Trueba, Iciar; Martı́n-Pérez, Jorge

doi:10.1210/me.2002-0422

Cited by 126 publications

(122 citation statements)

References 56 publications

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“…Second, in NMuMG cells, PRL activated PKC, but activated ERK only to a modest degree, and PRL dramatically inhibited EGFinduced Ras/ERK signaling (Johnson et al, 1996;Fenton and Sheffield, 1997). In contrast, we found that PRL promoted robust ERK and SHC activation in T47D cells, consistent with others' findings in these cells (Acosta et al, 2003), and that cotreatment with PRL and EGF augmented the SHC/ERK signaling. Finally, PRL decreased both basal and EGF-induced EGFR kinase activity in NMuMG cells (Quijano and Sheffield, 1998).…”

Section: Discussionsupporting

confidence: 91%

“…Here, we used the T47D human breast cancer cell line, which is a model system for studies of PRL and EGF action in breast cancer biology (Das and Vonderhaar, 1996a, b;Haraguchi et al, 1997;Gibson et al, 1999;Maus et al, 1999;Badache and Hynes, 2001;Lichtner et al, 2001;Chen et al, 2002;Chughtai et al, 2002;Kassenbrock et al, 2002;Acosta et al, 2003). We first tested responsiveness to each stimulus in these cells.…”

Section: Prl Promotes Erk-dependent Threonine Phosphorylation Of Egfrmentioning

confidence: 99%

“…Among other pathways, PRL activates the extracellular signal-regulated kinase (ERK) and STAT signaling pathways, with STAT5a being the principal STAT isoform involved in its mammary effects (Campbell et al, 1994;Rui et al, 1994;Liu et al, 1997;Clevenger and Kline, 2001). PRL induces ERK activity in several breast cancer cell lines, which may be important in PRL-induced biological effects in these cells (Das and Vonderhaar, 1996a, b;Llovera et al, 2000a;Schroeder et al, 2002;Acosta et al, 2003). In some cases, PRL synergizes with other growth factors in activating ERK (Clevenger et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

Huang

Jiang

et al. 2006

Oncogene

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Prolactin (PRL) is a polypeptide hormone produced by the anterior pituitary gland and other sites that acts both systemically and locally to cause lactation and other biological effects by interacting with the PRL receptor, a Janus kinase (JAK)2-coupled cytokine receptor family member, and activating downstream signal pathways. Recent evidence suggests PRL is a player in the pathogenesis and progression of breast cancer. Epidermal growth factor (EGF) also has effects on breast tissue, working through its receptors, epidermal growth factor receptor (EGFR) and ErbB-2 (c-neu, HER2), both intrinsic tyrosine kinase growth factor receptors. EGFR promotes pubertal breast ductal morphogenesis in mice, and both EGFR and ErbB-2 are relevant in pathogenesis and behavior of breast and other human cancers. Previous studies showed that PRL and EGF synergize to enhance motility in the human breast cancer cell line, T47D. In this study, we explored crosstalk between the PRL and EGF signaling pathways in T47D cells, with an ultimate aim of understanding how these two important factors might work together in vivo to affect breast cancer behavior. Both PRL and EGF caused robust signaling in T47D cells; PRL acutely activated JAK2, signal transducer and activator of transcription-5 (STAT5), and extracellular signal-regulated kinase-1 and -2 (ERK1 and ERK2), whereas EGF caused EGFR activation and consequent src homology collagen (SHC) activation and ERK activation. Notably, PRL also caused phosphorylation of the EGFR and ErbB-2 at sites detected by PTP101, an antibody that recognizes threonine phosphorylation at consensus motifs for ERK-induced phosphorylation. PRL-induced PTP101-reactive phosphorylation was prevented by pretreatment with PD98059, an ERK pathway inhibitor. Furthermore, PRL synergized with EGF in activating SHC and ERK and transactivating a luciferase reporter driven by c-fos gene enhancer elements, suggesting that PRL allowed markedly enhanced EGF signaling. This was accompanied by substantial inhibition of EGF-induced EGFR downregulation when PRL and EGF cotreatment was compared to EGF treatment alone. This effect of PRL was abrogated by ERK pathway inhibitor pretreatment. Our data suggest that PRL synergistically augments EGF signaling in T47D breast cancer cells at least in part by lessening EGF-induced EGFR downregulation and that this effect requires PRL-induced ERK activity and threonine phosphorylation of EGFR.

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Section: Discussionsupporting

confidence: 91%

Section: Prl Promotes Erk-dependent Threonine Phosphorylation Of Egfrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

Huang

Jiang

et al. 2006

Oncogene

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“…PRL treatment of T47D cells has been shown to result in tyrosine phosphorylation of paxillin (Canbay et al, 1997;Acosta et al, 2003); however, there are no reports of changes in paxillin serine/threonine phosphorylation in response to PRL. To evaluate this, untransfected and control siRNAtransfected T47D cells were stimulated with PRL, and anti-paxillin immunoprecipitates were examined for serine phosphorylation (Figure 5b).…”

Section: Nek3 Contributes To Prl-mediated Rac1 Activationmentioning

confidence: 98%

Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

et al. 2007

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Prolactin (PRL) stimulates the cytoskeletal re-organization and motility of breast cancer cells. During PRL receptor signaling, Vav2 becomes phosphorylated and activated, an event regulated by the serine/threonine kinase Nek3. Given the regulatory role of Vav2, the function of Nek3 in PRL-mediated motility and invasion was examined. Overexpression of Nek3 in Chinese hamster ovary transfectants potentiated cytoskeletal re-organization in response to PRL. In contrast, downregulation of Nek3 expression by small-interfering RNA (siRNA) attenuated PRL-mediated cytoskeletal reorganization, activation of GTPase Rac1, cell migration and invasion of T47D cells. In addition, PRL stimulation induced an interaction between Nek3 and paxillin and significantly increased paxillin serine phosphorylation, whereas Nek3 siRNA-transfected cells showed a marked reduction in paxillin phosphorylation. Analysis of breast tissue microarrays also demonstrated a significant up-regulation of Nek3 expression in malignant versus normal specimens. These data suggest that Nek3 contributes to PRLmediated breast cancer motility through mechanisms involving Rac1 activation and paxillin phosphorylation.

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“…In breast cancer cell lines PRL stimulates both the JAK1 and JAK2 pathways (Campbell et al, 1994;Liu et al, 1997;Neilson et al, 2007), and we have previously demonstrated that PRL stimulates Src kinases, which then independently activate Fak/ERK1/2 and the PI3K-dependent p70S6K and Akt kinases (Acosta et al, 2003). Activated ERK1/2 and AKT lead among others to increased AP-1 complexes, and induce the expression of cell-cycle progression genes such as cyclin D1 or c-myc (Brockman et al, 2002;Acosta et al, 2003;Gutzman et al, 2005).…”

Section: Introductionmentioning

confidence: 98%

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

et al. 2009

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Both prolactin (PRL) and estrogen (E2) are involved in the pathogenesis and progression of mammary neoplasia, but the mechanisms by which these hormones interact to exert their effects in breast cancer cells are not well understood. We show here that PRL is able to activate the unliganded estrogen receptor (ER). In breast cancer cells, PRL activates a reporter plasmid containing estrogen response elements (EREs) and induces the ER target gene pS2. These actions are blocked by the antagonist ICI 182,780, showing that ER is required for the PRLmediated effect. Moreover, PRL leads to phosphorylation of ERa in serine-118 (P-ERa), a modification related to the potentiation of ligand-independent transcriptional activation. In addition, PRL mimics the effect of E2 on target gene expression by inducing cyclical recruitment of ERa and P-ERa to ERE-containing promoters, resulting in recruitment of co-activators and acetylation of histone H3. Finally, PRL induces expression of c-Myc and Cyclin D1 and leads to increased cell proliferation, which is specifically antagonized by ICI 182,780 or ERa depletion. These results show that ligand-independent ERa activation appears to be an important component of the proliferative and transcriptional actions of PRL in breast cancer cells.

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Src Mediates Prolactin-Dependent Proliferation of T47D and MCF7 Cells via the Activation of Focal Adhesion Kinase/Erk1/2 and Phosphatidylinositol 3-Kinase Pathways

Cited by 126 publications

References 56 publications

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells

Activation of the unliganded estrogen receptor by prolactin in breast cancer cells

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