Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation

Maruani, Denise; Spiegel, Tirtza; Harris, E N; Shachter, Avielle; Unger, H A; Herrero-González, Sandra; Holz, Marina K.

doi:10.1038/onc.2011.657

Cited by 62 publications

(53 citation statements)

References 35 publications

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“…In addition, RPS6KB1 is a target gene for ER transcription (Maruani et al 2012). S6K2 has recently been brought to light as a potentially important oncoprotein, with fewer essential roles in normal tissue than S6K1, making it an interesting treatment target (Pardo & Seckl 2013).…”

Section: Introductionmentioning

confidence: 99%

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

Bostner¹,

Karlsson²,

Eding³

et al. 2015

Endocrine-Related Cancer

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Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, PZ0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, P!0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, PZ0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, PZ0.00041 (cytoplasm), PZ0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

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Section: Introductionmentioning

confidence: 99%

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

Bostner¹,

Karlsson²,

Eding³

et al. 2015

Endocrine-Related Cancer

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“…phosphorylated AKT and phosphorylated mTOR) in tumors after treatment, compared with pretreatment levels, was predictive of a better clinical outcome (Generali et al 2008(Generali et al , 2011, suggesting that estrogen via the ER was regulating these pathways, directly or indirectly in vivo. Many preclinical models have shown that estrogen, via ER signaling, at least in part, regulates the activities of PI3K/AKT/mTOR, p38MAPK, and MAPK/ ERK1/2 (Zhang et al 2002, Lee et al 2005, Yu & Henske 2006, Kazi et al 2009, Maruani et al 2012. This suggests that the use of hormonal therapies in combination with the most appropriately targeted kinase inhibitors may be more beneficial at the onset of therapy than application in a sequential fashion.…”

Section: Kinase Overexpression Associated With Sensitivity To Endocrimentioning

confidence: 99%

The kinome associated with estrogen receptor-positive status in human breast cancer

Bruce

McAllister

Murphy

2014

Endocrine Related Cancer

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Estrogen receptor alpha (ERa) regulates and is regulated by kinases involved in several functions associated with the hallmarks of cancer. The following literature review strongly suggests that distinct kinomes exist for ERa-positive and -negative human breast cancers. Importantly, consistent with the known heterogeneity of ERa-positive cancers, different subgroups exist, which can be defined by different kinome signatures, which in turn are correlated with clinical outcome. Strong evidence supports the interplay of kinase networks, suggesting that targeting a single node may not be sufficient to inhibit the network. Therefore, identifying the important hubs/nodes associated with each clinically relevant kinome in ERC tumors could offer the ability to implement the best therapy options at diagnosis, either endocrine therapy alone or together with other targeted therapies, for improved overall outcome.

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“…61 S6K1 can directly phosphorylate ERα on Ser167; conversely, ERα activation leads to increased S6K1 expression, resulting in a positive coregulatory loop. 18,19,61 Thus, it appears may play a secondary or indirect role. 19,39 Importantly, this site is associated with tamoxifen resistance.…”

Section: S6k1 In Er-positivementioning

confidence: 99%

“…For that S6K1 expression is maintained in two modes: a basal level of expression, typical of normal cells, and an estrogen/ ERα-dependent specific upregulation. 61 Others have observed estrogen-mediated regulation of RPS6KB1 transcription in ZR-75-1 and MCF7 ER-positive breast cancer cell lines. 62,63 The estrogenic mode of S6K1 upregulation does not seem to be limited to breast epithelia.…”

Section: S6k As a Prognostic And A Therapeutic Target In Breast Cancermentioning

confidence: 99%

“…40 Moreover, we have shown that S6K1 expression is estrogenically regulated via ERα. 61 Inhibition of the estrogenic activation of S6K1 may also be the target of action of letrozole, which has been shown to reduce phosphorylation of S6K1 and its targets, p-mTOR Ser2448 and p-S6. 48,73,79 Therefore, maintaining high co-overexpression of both S6K1 and ERα may provide a selective advantage for breast cancer cells and contribute to disregulated proliferation of cells during the progression to carcinogenesis and breast cancer.…”

Section: Grant Supportmentioning

confidence: 99%

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The role of S6K1 in ER-positive breast cancer

Holz

2012

Cell Cycle

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T he 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt and many others. S6K1 is the principal kinase effector downstream of the mammalian target of rapamycin complex 1 (mTORC1). S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis and cell migration and invasion. Several lines of evidence suggest an important role for S6K1 in estrogen receptor (ER)-positive breast cancer. S6K1 directly phosphorylates and activates ERα. Furthermore, S6K1 expression is estrogenically regulated. Therefore, hyperactivation of mTORC1/ S6K1 signaling may be closely related to ER-positive status in breast cancer and may be utilized as a marker for prognosis and a therapeutic target. IntroductionThe mTORC1 signaling pathway. Since its cloning and biochemical purification almost 20 y ago, mTOR, a conserved protein kinase, emerged as a central node in the plexus coordinating cellular growth and proliferation in response to numerous extracellular cues, including nutrient availability and growth stimuli. In eukaryotic cells, mTOR exists in two complexes. mTORC1 and mTORC2 consist of distinct sets of proteins and perform non-redundant functions. 1 a naturally derived inhibitor of mTORC1 and an inhibitor of cell proliferation, as manifested by its potent immunosuppressive properties and activity against solid tumors. 2 Growth factor signaling to mTORC1 is primarily mediated by the phosphatidylinositol-3 kinase (PI3K) pathway and inactivation of the tuberous sclerosis complex protein TSC2 (tuberin). As illustrated in Figure 1, in response to extracellular activating stimuli, PI3K mediates cell membrane recruitment and activation of the serine/threonine protein kinases phosphatidylinositol-dependent kinase-1 (PDK1) and Akt. 3,4 The lipid phosphatase PTEN opposes the action of PI3K. TSC2 functions as a heterodimer with TSC1 (hamartin) to negatively regulate mTORC1 signaling by acting as a GTPase-activating protein (GAP) for the small GTPase Rheb. 5 Rheb directly binds to mTORC1 and regulates its activity in a GTP-dependent manner. 6 Thus, TSC2 inhibits Rheb-dependent activation of mTORC1. Phosphorylation and inactivation of TSC2 has first been shown to occur via PI3K/Akt. 7 Subsequently, several groups have shown that the Ras/ERK pathway also converges on the TSC1/2 complex. Ras-activated ERK1/2 directly phosphorylates TSC2 at sites different than Akt, resulting in TSC2 inactivation. 8 The downstream effector of ERK, RSK, also phosphorylates TSC2 at a unique site, thus inactivating it. 9 Therefore, TSC2 serves as a convergence point for multiple signaling inputs to mTORC1.Activation of S6K1. S6K1 is one of the best-characterized downstream targets of mTORC1, and rapamycin treatment re...

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Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation

Cited by 62 publications

References 35 publications

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

The kinome associated with estrogen receptor-positive status in human breast cancer

The role of S6K1 in ER-positive breast cancer

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