Sprouty genes function in suppression of prostate tumorigenesis

Abstract

Expression of Sprouty genes is frequently decreased or absent in human prostate cancer, implicating them as suppressors of tumorigenesis. Here we show they function in prostate tumor suppression in the mouse. Concomitant inactivation of Spry1 and Spry2 in prostate epithelium causes ductal hyperplasia and low-grade prostatic intraepithelial neoplasia (PIN). However, when Spry1 and Spry2 loss-of-function occurs in the context of heterozygosity for a null allele of the tumor suppressor gene Pten, there is a striking increase in PIN and evidence of neoplastic invasion. Conversely, expression of a Spry2 gain-of-function transgene in Pten null prostatic epithelium suppresses the tumorigenic effects of loss of Pten function. We show that Sprouty gene loss-of-function results in hyperactive RAS/ERK1/ 2 signaling throughout the prostate epithelium and cooperates with heterozygosity for a Pten null allele to promote hyperactive PI3K/AKT signaling. Furthermore, Spry2 gain-of-function can suppress hyperactivation of AKT caused by the absence of PTEN. Together, these results point to a key genetic interaction between Sprouty genes and Pten in prostate tumorigenesis and provide strong evidence that Sprouty genes can function to modulate signaling via the RAS/ERK1/2 and PI3K/AKT pathways. The finding that Sprouty genes suppress tumorigenesis caused by Pten loss-of-function suggests that therapeutic approaches aimed at restoring normal feedback mechanisms triggered by receptor tyrosine kinase signaling, including Sprouty gene expression, may provide an effective strategy to delay or prevent high-grade PIN and invasive prostate cancer. P rostate cancer is the most commonly diagnosed malignancy in men, with more than 240,000 new diagnoses anticipated in 2012. Despite advances in both diagnosis and treatment, ∼28,000 prostate cancer deaths are expected in the United States in 2012 (1). Although androgen deprivation remains a cornerstone of therapy, inevitably the disease becomes resistant to interventions aimed at depleting androgens and treatments are limited for this lethal form of the disease. A better understanding of the genetic and molecular basis for prostate cancer may lead to more effective therapies and prevention strategies.The tumor suppressor gene PTEN, which encodes a key negative regulator of PI3 kinase (PI3K)/AKT signaling, is frequently deleted or mutated in human prostate cancer, resulting in increased AKT activity (2, 3). The importance of PTEN in prostate cancer has been demonstrated in the mouse, where loss of Pten function can recapitulate the progression of the human disease from prostatic intraepithelial neoplasia (PIN) to invasive cancer (4, 5). In addition to increased PI3K/AKT activity, a common feature of aggressive human prostate cancers is hyperactivation of the RAS/ ERK1/2 pathway (6). However, oncogenic mutations in RAS or RAF are rare and the molecular basis for aberrant ERK1/2 activity in human prostate cancer is unknown (7,8).One possible mechanism for RAS/ERK1/2 pathway hyperactivation is loss-o...

Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumorigenesis

“…These data are in agreement with two recent reports showing that deletion of Spry family members in the context of Pten happloinsuficiency accelerates prostate tumorigenesis. 51,52 During the last years, it is becoming evident that OIS poses a potent barrier to tumoral transformation in vivo. Thus, the expression of activated Ras, E2f3 or B-Raf oncogenes in mice induces cellular senescence in premalignant tumors of the lung, pancreas, mammary gland, pituitary gland and melanoma.…”

ERKs in Cancer: Friends or Foes?

“…The genetic ablation of both Spry1 and Spry2 alleles, which are negative regulators of RTK signaling, leads to the expected increase in pERK levels, but no significant regulation of AKT signaling was observed in the prostate. This context induced frequent ductal hyperplasia, occasionally progressing into low-grade prostatic intraepithelial neoplasia (PIN) lesions (66). These lesions were previously shown to display markers of senescence (67).…”

MiR-122 promotes renal cancer cell proliferation by targeting Sprouty2

“…22,[25][26][27][28][29] Some sprouty proteins can specifically inhibit the Ras/MAPK signaling pathway and regulate pivotal signaling pathways that are essential to cancer oncogenesis or neoplasia, including angiogenesis, cytokinesis, cell proliferation, invasion, and migration. 18,[20][21][22]24,26,31,32 We found that Spry2 expression level was significantly lower in tumors than in adjacent non-cancer tissue samples, supporting its role as a tumor suppressor in RCC. Additionally, we confirmed that the inhibition of miR-122 promoted the expression of Spry2, suggesting that miR-122 may be involved in regulating malignant biological activity.…”