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

Miller, Sommer; Antico, Giovanni; Raghunath, Puthiyaveettil N.; Tomaszewski, John E.; Clevenger, Charles V.

doi:10.1038/sj.onc.1210264

Cited by 79 publications

(71 citation statements)

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“…The localization of Vav family members in association with the cell membrane, and in the cytoplasm and nucleus have been previously reported. 3 Rho/Rac proteins are essential for the formation of cytoskeletal structures that contribute to changes in cell shape and motility, the activation of lipid and protein kinase cascades, and the induction of patterns of gene expression required for developmental and proliferative decisions. 16 Activation of Rho/Rac proteins also can lead to cellular transformation and oncogenesis, either by enhancing the metastatic properties of transformed cells or by serving as secondary factors that contribute to the transforming activities of oncoproteins such as Ras.…”

Section: Discussionmentioning

confidence: 99%

“…Although the visual scoring data disagreed with our hypothesis by showing a decrease in the expression of Vav2, the data did not achieve statistical significance (P ¼ 0.107). An alternative hypothesis that may explain these data is that regulation of Vav2 activity may be controlled by post-translational mechanisms, such as serine and tyrosine phosphorylation, 2,3 as is mediated by the Nek3 kinase. Further investigation of the post-translational alterations of Vav2 is currently planned.…”

Section: Discussionmentioning

confidence: 99%

“…2 Like Vav2, Nek3 has been observed in the cytoplasm and the nucleus. 2,3 In addition, Nek3 has been found to associate with and contribute to the phosphorylation of the critical integrator of cell adhesion, paxillin. 3 Thus, through its actions on Vav2 and paxillin, Nek3 may contribute to the oncogenesis of breast cancer.…”

Section: Signaling In Breast Cancer K Mchale Et Almentioning

confidence: 99%

“…1 In malignant tissues, however, prolactin fails to trigger differentiation, and instead enhances breast epithelial survival and motility. [2][3][4] Both normal and malignant breast epithelia, besides responding to pituitary-secreted (endocrine) prolactin, synthesize prolactin RNA from an upstream promoter at the autocrine/paracrine level. 4 As mutations of the prolactin receptor are very infrequent in breast cancer, we hypothesized that dysregulation of local prolactin production or prolactin receptor-associated signaling machinery may contribute to some of the altered actions of prolactin in this disease.…”

mentioning

confidence: 99%

“…5 Previous studies from our laboratory have demonstrated a significant stimulatory role for both serine-threonine kinase Nek3 and the guanine nucleotide exchange factor Vav2 in the regulation of the actin cytoskeleton and cell motility and survival via the small GTP-binding protein Rac. 2,3 Signal regulatory protein a (SIRP) is a prolactin receptor-and growth hormone receptor-associated signaling protein that regulates the growth hormone and prolactin-induced Jak2 signaling in an extracellular matrix-dependent manner and may mediate crosstalk between integrins and the prolactin receptor. 6,7 The transcription factor Stat5 mediates many of the nuclear actions of prolactin; 8 its expression has been recently associated with well-differentiated breast cancers.…”

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confidence: 99%

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Altered expression of prolactin receptor-associated signaling proteins in human breast carcinoma

et al. 2008

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Prolactin receptor signaling can modulate proliferation, survival, motility, angiogenesis, and differentiation in breast cancer. Increased serum prolactin is associated with a significantly increased risk of breast cancer in post-menopausal women. The purpose of this study was to examine the expression of prolactin receptorassociated signaling proteins in breast cancer vs benign breast tissue. Breast tissue microarrays representing 40 cases of benign and malignant pathologies were obtained from the Cooperative Human Tissue Network. Standard immunohistochemistry for prolactin and prolactin receptor-associated proteins was performed. Both positive regulators (c-Myb, Nek3, Vav2) and negative regulators (PIAS3, SIRP) of prolactin receptor signaling were examined. Virtual slides were created from the stained breast tissue microarrays. Labels were scored by region of interest and labeling indices incorporating percent target labeled and label intensity were created. Quantitative determinations of labels were made using the Clarient image system. The unpaired t-test was used to compare labels from benign and malignant tissues. Visual scoring data showed upregulation of Nek3 (P ¼ 0.000377), PIAS3 (P ¼ 0.000257), and prolactin (P ¼ 0.002576) in breast cancer vs normal/hyperplastic epithelium. c-Myb showed a trend toward upregulation, but this did not achieve statistical significance (P ¼ 0.107374). SIRP (P ¼ 0.002060) was downregulated. Vav2 showed a trend toward downregulation (P ¼ 0.107456), but this did not achieve statistical significance. Clarient analysis corroborated upregulation in cancer of Nek3 (P ¼ 0.000013), PIAS3 (P ¼ 0.000067), and prolactin (P ¼ 0.017569). In conclusion, regulators of prolactin receptor signaling show heterogeneity in their expression in benign vs malignant breast tissue. Since these species are known to regulate prolactin-mediated actions, these results suggest multiple targets for modulating prolactin receptor-mediated growth and differentiation in breast cancer. The neuroendocrine hormone prolactin contributes to breast cancer progression through both endocrine and autocrine/paracrine loops. Prolactin acts through its cell-surface receptor, the prolactin receptor, and triggers a network of prolactin receptor-associated signaling proteins. In normal tissues, prolactin stimulates lobulo-alveolar expansion and differentiation as a prelude to milk synthesis and secretion. 1 In malignant tissues, however, prolactin fails to trigger differentiation, and instead enhances breast epithelial survival and motility. [2][3][4] Both normal and malignant breast epithelia, besides responding to pituitary-secreted (endocrine) prolactin, synthesize prolactin RNA from an upstream promoter at the autocrine/paracrine level. 4 As mutations of the prolactin receptor are very infrequent in breast cancer, we hypothesized that dysregulation of local prolactin production or prolactin receptor-associated signaling machinery may contribute to some of the altered actions of prolactin in this disease.This study focus...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%