CoChat
Sign Up
Cited by 136PI3K/AKT/mTOR signaling in cancerBreast Cancer Treatment StudiesHippo pathway signaling and YAP/TAZ

Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer

Open access
Feigin, Michael E., Akshinthala, S. Dipikaa, Araki, Kiyomi, Rosenberg, Avi Z., Muthuswamy, Lakshmi B., Martin, Bernard, Lehmann, Brian D., Berman, Hal K. +3 more·2014·Cancer Research
DOI 10.1158/0008-5472.can-13-3415PMC PMC4096808

Published version of a preprint

Open this paper in CoChat — free account

Abstract

Scribble (SCRIB) localizes to cell–cell junctions and regulates establishment of epithelial cell polarity. Loss of expression of SCRIB functions as a tumor suppressor in Drosophila and mammals; conversely, overexpression of SCRIB promotes epithelial differentiation in mammals. Here, we report that SCRIB is frequently amplified, mRNA overexpressed, and protein is mislocalized from cell–cell junctions in human breast cancers. High levels of SCRIB mRNA are associated with poor clinical prognosis, identifying an unexpected role for SCRIB in breast cancer. We find that transgenic mice expressing a SCRIB mutant [Pro 305 to Leu (P305L)] that fails to localize to cell–cell junctions, under the control of the mouse mammary tumor virus long terminal repeat promoter, develop multifocal hyperplasia that progresses to highly pleomorphic and poorly differentiated tumors with basal characteristics. SCRIB interacts with phosphatase and tensin homolog (PTEN) and the expression of P305L, but not wild-type SCRIB, promotes an increase in PTEN levels in the cytosol. Overexpression of P305L, but not wild-type SCRIB, activates the Akt/mTOR/S6K signaling pathway. Human breast tumors overexpressing SCRIB have high levels of S6K but do not harbor mutations in PTEN or PIK3CA, identifying SCRIB amplification as a mechanism of activating PI3K signaling in tumors without mutations in PIK3CA or PTEN. Thus, we demonstrate that high levels of mislocalized SCRIB functions as a neomorph to promote mammary tumorigenesis by affecting subcellular localization of PTEN and activating an Akt/mTOR/S6kinase signaling pathway. Cancer Res; 74(11); 3180–94. ©2014 AACR.

Integrity signals

Registry

Crossref · 10.1158/0008-5472.can-13-3415

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Of 20 breast cancer samples with moderate to strong SCRIB, 11 had mainly cytosolic SCRIB and 9 had both membrane and cytosolic SCRIB.

    “11 of the 20 samples showed predominantly cytosolic SCRIB localization (Fig. 1Eiii), while the remaining nine showed a combination of membrane and cytosolic localization (Fig. 1Ei,ii).”
    Quote in the paperSubstantial claim
  • Findingown data

    Mice engineered to express hSCRIBP305L via the MMTV LTR develop multifocal hyperplasia.

    “transgenic mice expressing a SCRIB mutant (Pro 305 to Leu (P305L)) that fails to localize to cell-cell junctions, under the control of the mouse mammary tumor virus long terminal repeat promoter, develop multifocal hyperplasia”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The tumorigenic effect in hSCRIBP305L mice is attributable to SCRIB mislocalization rather than to SCRIB overexpression alone.
  • Findingown data

    In MCF-10A cells expressing wild-type SCRIB, EGF caused a threefold rise in Ser473 phosphorylation by 2.5 minutes, peaking at 5 minutes.

    “In cells expressing SCRIBWT, addition of EGF led to three-fold increase Ser473 phosphorylation within 2.5 minutes, with a peak at 5 minutes after stimulation.”
    Quote in the paperSubstantial claim
  • Findingown data

    In parental MCF-10A cells, an EGF-induced increase in Akt substrate phosphorylation was detectable at 30 minutes.

    “In parental MCF-10A cells, an EGF stimulation-induced increase in substrate phosphorylation was detectable by 30 minutes.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Mammary glands from hSCRIBP305L mice had more SCRIB protein than those from control mice.

    “hSCRIBP305L mice displayed higher levels of SCRIB protein in the mammary gland than control mice.”
    Quote in the paperSubstantial claim
  • May combine two claims. 43
  • Classified as probably not a substantial claim. 12
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    MDA-MB-231, T47D, and MCF7 cancer cell lines all had mislocalized SCRIB, with no mutations in the Pro 305-containing LRR domain.

    “While the cancer cell lines all showed mislocalized SCRIB, no mutations within the Pro 305-containing LRR domain were found (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The 14 hSCRIBP305L tumors included adenocarcinomas (29%), spindle cell tumors (14%), adenosquamous carcinoma (21%), cystic squamous cell carcinoma (14%), and unclassified cases (21%).

    “The tumors were broadly classified as adenocarcinomas (29%), spindle cell tumors (14%), adenosquamous carcinoma (21%), and cystic squamous cell carcinoma (14%), while the remainder did not fall into simple classification (21%) (Fig. 5C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In MCF-10A cells expressing hSCRIBP305L, Ser473 phosphorylation rose ninefold at 2.5 minutes, stayed elevated through 5 minutes, and fell by 15 minutes.

    “MCF-10A cells expressing hSCRIBP305L displayed a nine fold increase of Ser473 phosphorylation at 2.5 minutes that was maintained through 5 minutes and decreased by 15 minutes”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    In MCF-10A cells, EGF stimulation caused ERK phosphorylation by 2.5 minutes that persisted to 15 minutes.

    “EGF-stimulation of MCF-10A cells promoted ERK phosphorylation within 2.5 minutes, which was maintained through 15 minutes (Fig. 6C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Human breast tumors with SCRIB overexpression show high S6K and lack PTEN or PIK3CA mutations.

    “Human breast tumors overexpressing SCRIB have high levels of S6K but do not harbor mutations in PTEN or PIK3CA”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    P305L overexpression, but not wild-type SCRIB overexpression, turns on Akt/mTOR/S6K signaling.

    “Overexpression of P305L, but not wild type SCRIB, activates the Akt/mTOR/S6K signaling pathway.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Overexpressed SCRIBWT goes to the cell membrane and concentrates at cell-cell junctions, while hSCRIBP305L is mainly cytosolic.

    “Overexpressed SCRIBWT localizes to the cell membrane and is concentrated at cell-cell junctions, whereas hSCRIBP305L is predominantly localized to the cytosol (Fig. 6B).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    hSCRIBP305L cells showed enhanced S6 phosphorylation compared with parental or wild-type SCRIB cells.

    “Consistently, MCF-10A cells expressing hSCRIBP305L displayed enhanced phosphorylation of S6, as compared with parental MCF-10A cells or MCF-10A cells expressing SCRIBWT (Fig. 6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In MCF-10A cells, EGF induced PRAS40 phosphorylation within 2.5 minutes, which returned near baseline by 30 minutes.

    “In MCF-10A cells, EGF stimulation induced PRAS40 phosphorylation within 2.5 minutes, returning to near basal levels by 30 minutes (Fig. 6D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Histological features varied both between tumors and within tumors.

    “We observed both inter-tumor and intra-tumor heterogeneity for histological characteristics (Fig. 5B, insets).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    hSCRIBP305L tumors had less E-cadherin and more Vimentin and CK14.

    “hSCRIBP305L tumors expressed lower levels of E-cadherin and high levels of Vimentin and CK14.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adding EGF to MCF-10A cells raised Akt308 phosphorylation by 2.5 minutes, it fell after 5 minutes, and returned to baseline by 15 minutes.

    “Addition of EGF to the cells led to an increase in Akt308 phosphorylation within 2.5 minutes, reduced after 5 minutes and returned to basal levels by 15 minutes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In hSCRIBP305L mice, CD49flo/CD61+ cells made up 17.1% of the population, 57% more than in FVB controls.

    “This population accounted for 17.1% of cells in hSCRIBP305L mice, a 57% increase over FVB controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hyperplastic hSCRIBP305L mammary glands had more CK18-positive and double-positive cells and fewer CK14-positive cells.

    “In contrast, hyperplastic hSCRIBP305L mammary glands showed increased levels of CK18-positive and double positive cells, with a decrease in the percentage of CK14-positive cells (Fig. 4D,E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In human breast cancers, SCRIB is often amplified, its mRNA is over-expressed, and its protein is mislocalized away from cell-cell junctions.

    “SCRIB is frequently amplified, mRNA over-expressed and protein is mislocalized from cell-cell junctions in human breast cancers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 748 breast cancer samples, SCRIB was amplified in 116 (15.6%), homozygously deleted in two (0.3%), and had a somatic frame shift mutation in one.

    “Among the 748 breast cancer samples analyzed, SCRIB was amplified in 116 tumors (15.6%), homozygous deleted in two (0.3%) and contained a somatic frame shift mutation in one (Fig. 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In wild-type SCRIB cells, EGF induced PRAS40 phosphorylation with similar kinetics and intensity, but it was greater at 30 minutes.

    “In MCF-10A cells expressing SCRIBWT, EGF induced PRAS40 phosphorylation with similar kinetics and intensity but greater at 30 minutes after EGF-stimulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ductal structures from 20-week-old hSCRIBP305L mice had markedly higher pS6 staining than controls, and this remained elevated through 50 weeks.

    “However, ductal structures from 20-week old hSCRIBP305L mice displayed markedly higher pS6 staining than controls, and maintained this enhanced signal through 50 weeks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SCRIB amplification did not correlate with PTEN mutations (P=0.2, n=760) or PIK3CA mutations (p=0.3, n=482).

    “Interestingly, there was no correlation between amplification of SCRIB and mutations in PTEN (P=0.2, n=760) and PIK3CA (p=0.3, n=482), regulators of the PI3K signaling pathway,”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    T7-SCRIB pulled down wild-type PTEN but significantly less PTEN-399.

    “T7-SCRIB was able to pull down WT-PTEN, but significantly less PTEN-399, demonstrating that the C-terminal PDZ binding site of PTEN is critical for the SCRIB/PTEN interaction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Wild-type PTEN, but not PTEN-399, attenuated EGF-induced Akt phosphorylation.

    “Expression of WT-PTEN, but not PTEN-399, attenuated EGF-induced phosphorylation of Akt (Fig. 7G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both wild-type SCRIB and hSCRIBP305L pulled down PTEN.

    “Importantly, both SCRIBWT and hSCRIBP305L were able to pull down PTEN.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Akt phosphorylates PRAS40 at Thr246, which relieves PRAS40's inhibition of mTORC1.

    “Akt directly phosphorylates PRAS40 at Thr246, relieving the PRAS40 inhibitory effect on the mTOR1 complex (mTORC1) (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Sancak, 2007, PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase, Mol Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The tumor cells are malignant and can extravasate from the primary site.

    “suggesting that the tumor cells are not benign and have the capacity to extravasate from the primary site.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overexpression of SCRIB promotes epithelial differentiation in mammals.

    “overexpression of SCRIB in mammary epithelial cells promotes epithelial differentiation by suppressing expression of epithelial mesenchymal transition regulators in a Ras/MAPK dependent manner (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Elsum, 2013, Scribble regulates an EMT polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation, J Cell Sci

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of SCRIB expression functions as a tumor suppressor in Drosophila and mammals.

    “Loss of SCRIB that results in uncontrolled proliferation and tissue growth identifying it as tumor suppressor (1).”
    • Also stated in: § Introduction · plain
      “In mammals, loss of SCRIB induces dysplastic growth in vivo (2, 3) identifying loss of expression as a tumor suppressive mechanism.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Bilder, 2000, Localization of apical epithelial determinants by the basolateral PDZ protein Scribble, Nature source

      Not checked in the free run.

    • cites [2] Zhan, 2008, Deregulation of Scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma, Cell source

      Not checked in the free run.

    • cites [3] Pearson, 2011, SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia, J Clin Invest source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mTOR phosphorylates p70S6K at multiple residues, increasing its kinase activity.

    “mTOR phosphorylates p70S6 kinase (p70S6K) at several residues, resulting in increased kinase activity (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Pullen, 1998, Phosphorylation and activation of p70s6k by PDK1, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Akt kinase is activated early in both wild-type SCRIB and hSCRIBP305L cells, but the activation lasts longer in hSCRIBP305L cells.

    “suggesting that Akt kinase is activated early in both SCRIBWT and hSCRIBP305L expressing cells but sustained longer in cells expressing hSCRIBP305L.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Akt phosphorylation at Thr308 and Ser473 is associated with increased Akt kinase activity.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Active p70S6K phosphorylates ribosomal protein S6, which increases translation of mRNAs involved in cell cycle progression.

    “Active p70S6K phosphorylates the ribosomal protein S6, enhancing translation of mRNA transcripts involved in cell cycle progression (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Jefferies, 1997, Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k, EMBO J source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Akt phosphorylates TSC2 at Thr1462, leading to mTORC1 activation.

    “Akt directly phosphorylates TSC2 at Thr1462, resulting in activation of mTORC1 (29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Manning, 2002, Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway, Mol Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    SCRIB overexpression is linked to aggressive breast cancer forms and poor clinical prognosis.

    “These observations demonstrate that SCRIB overexpression is associated with the aggressive forms of breast cancers and with poor clinical prognosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    hSCRIBP305L expression causes mammary tumors, which directly supports a causal role for SCRIB mislocalization in tumorigenesis.

    “We show that expression of hSCRIBP305L induces mammary tumors, providing direct evidence that SCRIB mislocalization can have a causal role during tumorigenesis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The tumorigenic effect in hSCRIBP305L mice is attributable to SCRIB mislocalization rather than to SCRIB overexpression alone.
    • Rests on an assumption: The hSCRIBP305L transgene is the cause of the mammary tumors, not spontaneous or insertional mutagenesis.

  • May combine two claims.

    Premisecitation

    A P305L mutation in human SCRIB's LRR13 prevents membrane localization and disrupts βPIX recruitment and exocytosis.

    “A specific point mutation within LRR13 (Prol 305 to Leu, P305L) of the human SCRIB protein (hSCRIB) has also been shown to abrogate membrane localization (13), disrupting recruitment of βPIX, and exocytosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Audebert, 2004, Mammalian Scribble forms a tight complex with the βPIX exchange factor, Curr Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    SCRIB mislocalization produces histologically diverse mammary tumors that have basal features.

    “Taken together, our data provide evidence that SCRIB mislocalization induces histologically diverse mammary tumors with basal characteristics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Mislocalized SCRIB at high levels acts as a neomorph that drives mammary tumorigenesis by altering PTEN's subcellular location and turning on Akt/mTOR/S6K signaling.

    “Thus, we demonstrate that high levels of mislocalized SCRIB functions as a neomorph to promote mammary tumorigenesis by affecting subcellular localization of PTEN and activating an Akt/mTOR/S6kinase signaling pathway.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The tumorigenic effect in hSCRIBP305L mice is attributable to SCRIB mislocalization rather than to SCRIB overexpression alone.

  • May combine two claims.

    Premisecitation

    In 3D MCF-10A cultures, wild-type hSCRIB overexpression did not affect morphogenesis, but hSCRIBP305L expression led to defective morphogenesis.

    “overexpression of wild-type hSCRIB in MCF-10A mammary epithelial cells grown in 3D had no impact on morphogenesis, whereas expression of hSCRIBP305L displayed defective morphogenesis (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Zhan, 2008, Deregulation of Scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma, Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The kinase mTORC2, acting in a rapamycin-insensitive complex, phosphorylates Akt at Ser473.

    “Akt is also phosphorylated within the carboxyl-terminal hydrophobic motif at Ser473 by the serine/threonine kinase mammalian target of rapamycin complex 2 (mTORC2), within a rapamycin-insensitive protein complex (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Sarbassov, 2005, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Scribble is required for directional migration, promotes epithelial identity, and suppresses epithelial-to-mesenchymal transition in mammary and corneal epithelial cells.

    “In addition, Scribble is required for directional migration, promotes epithelial identity and suppresses epithelial to mesenchymal transition in mammary and corneal epithelial cells (4, 5, 39).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Elsum, 2013, Scribble regulates an EMT polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation, J Cell Sci

      Not checked in the free run.

    • cites [5] Yamben, 2013, Scrib is required for epithelial cell identity and prevents epithelial to mesenchymal transition in the mouse, Dev Biol source

      Not checked in the free run.

    • cites [39] Dow, 2007, The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge, Oncogene source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Loss or downregulation of SCRIB acts as a tumor suppressor by inhibiting cell death or inducing proliferation.

    “Others and we have previously reported that downregulation (or loss) of SCRIB expression functions as a tumor suppressor by inhibiting cell death or inducing proliferation (2, 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Zhan, 2008, Deregulation of Scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma, Cell source

      Not checked in the free run.

    • cites [3] Pearson, 2011, SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Cancer genome analysis identifies SCRIB amplification and overexpression as frequent and clinically relevant in breast cancer, rather than deletion or decreased expression.

    “As we report here, large-scale cancer genome analysis identifies SCRIB gene amplification and overexpression as a frequent and clinically relevant event in breast cancer and not deletion or decrease in gene expression, raising new questions on how SCRIB may regulate the biology of cancer cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent analysis found that the PI3K/Akt pathway is elevated in basal-like cancers compared with luminal or HER2+ cancers.

    “A recent analysis, combining mutation, mRNA expression and protein levels, determined that the PI3K/Akt pathway was elevated in basal-like cancers as compared with luminal or HER2+ (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Cancer Genome Atlas Network, 2012, Comprehensive molecular portraits of human breast tumours, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These outgrowths had increased basal markers and decreased luminal markers, similar to findings with SCRIB mislocalization.

    “These outgrowths displayed increased basal markers (smooth muscle actin, CK5, CK6) and decreased luminal markers (estrogen receptor, CK18), similar to our findings with mislocalization of SCRIB.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Korkaya, 2009, Regulation of mammary stem/progenitor cells by PTEN/Akt/β-catenin signaling, PLoS Biol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Proper vesicle trafficking is critical for maintaining epithelial polarity.

    “In support of this hypothesis, proper vesicle trafficking is critical for maintenance of epithelial polarity (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Mellman, 2008, Coordinated protein sorting, targeting and distribution in polarized cells, Nat Rev Mol Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The gain of function from hSCRIBP305L likely drives tumorigenesis and contributes to invasive behavior in mammary tumors.

    “It is likely that the gain of function associated with hSCRIBP305L drives tumorigenesis and contributes to the invasive behavior observed in mammary tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mice with mammary PTEN deletion developed pathologically heterogeneous tumors with high basal marker expression.

    “Mice in which PTEN was deleted within the mammary epithelium developed pathologically heterogeneous tumors with high expression of basal markers (46).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Li, 2002, Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland, Development source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Mice overexpressing SCRIB activate a PI3K/S6K pathway and develop mammary tumors with a basal subtype.

    “and that mice overexpressing SCRIB activate a PI3K/S6K pathway and induce formation of mammary tumors with the basal subtype.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Akt phosphorylation at Thr308 and Ser473 is associated with increased Akt kinase activity.

  • May combine two claims.

    Interpretationown data

    Overexpressed mislocalized SCRIB acts as a neomorph by interacting with PTEN.

    “We demonstrate that overexpression of a mislocalized form of SCRIB functions as a neomorph by interacting with another tumor suppressor, PTEN, and activating an mTORC1/Akt/S6K signaling pathway in culture and in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    SCRIB normally promotes epithelial differentiation, and its loss leads to mesenchymal transition and tumorigenesis.

    “Together, these observations suggest a working model that SCRIB normally promotes epithelial differentiation and loss of expression results in mesenchymal transition and tumorigenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PTEN knockdown in mammary epithelial cells in 3D culture causes hyperproliferation and disrupted acinar organization.

    “Furthermore, knockdown of PTEN in mammary epithelial cells grown in 3D culture results in hyperproliferation and disrupted acinar organization (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Stiles, 2004, PTENless means more, Dev Biol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PTEN loss increases PIP3-mediated signaling, including Akt phosphorylation and activation.

    “Loss of PTEN enhances PIP3-mediated signaling, including phosphorylation and activation of Akt (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Wu, 1998, The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    PTEN is a phosphatase that dephosphorylates PIP3, a second messenger made by PI3K.

    “PTEN is a phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a second messenger generated by phosphoinositide 3-kinase (PI3K) (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Maehama, 1998, The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate, J Biol Chem source

      Not checked in the free run.

51 of 51

  • The paper relies on this without support.

    The tumorigenic effect in hSCRIBP305L mice is attributable to SCRIB mislocalization rather than to SCRIB overexpression alone.

    “To investigate the effect of expressing Scribble that does not localize to cell-cell junctions, we generated a transgenic mouse expressing hSCRIBP305L”

  • The paper relies on this without support.

    The hSCRIBP305L transgene is the cause of the mammary tumors, not spontaneous or insertional mutagenesis.

    “Virgin hSCRIBP305L mice, but not FVB control mice, developed regions of hyperplastic growth”

  • The paper relies on this without support.

    Akt phosphorylation at Thr308 and Ser473 is associated with increased Akt kinase activity.

    “Phosphorylation of Akt at 308 and 473 is associated with an increase in its kinase activity.”

  • The paper relies on this without support.

    SCRIB mislocalization is highly prevalent in human tumors.

    “Therefore, multiple distinct mechanisms may account for the high prevalence of SCRIB mislocalization observed human tumors.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Membrane localization is key to Scrib's tumor-suppressing activity.

    “The tumor-suppressive activity of Scrib correlates with its membrane localization.”

    From Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1 (2023) · cites this paper as [18]

    Experimental — accuracy not yet measured

  • Ectopic expression of Scrib/P305L in cell lines enhances Akt signaling.

    “Importantly, ectopic expression of Scrib/P305L in cell lines disrupts cell polarity, suppresses c-myc-induced apoptosis, enhances Akt signaling, and fails to suppress Ras-MAPK-induced EMT18,47,56,68.”

    From Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1 (2023) · cites this paper as [18]

  • Ectopic expression of Scrib/P305L in cell lines disrupts cell polarity.

    “Importantly, ectopic expression of Scrib/P305L in cell lines disrupts cell polarity, suppresses c-myc-induced apoptosis, enhances Akt signaling, and fails to suppress Ras-MAPK-induced EMT18,47,56,68.”

    From Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1 (2023) · cites this paper as [18]

  • Transgenic mice expressing Scrib/P305L in the mammary gland display hyperplastic growth in the mammary gland and develop mammary tumors.

    “Also, transgenic mice expressing Scrib/P305L in the mammary gland display hyperplastic growth in the mammary gland and develop mammary tumors18.”

    From Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1 (2023) · cites this paper as [18]

  • Ectopic expression of Scrib/P305L in cell lines suppresses c-myc-induced apoptosis.

    “Importantly, ectopic expression of Scrib/P305L in cell lines disrupts cell polarity, suppresses c-myc-induced apoptosis, enhances Akt signaling, and fails to suppress Ras-MAPK-induced EMT18,47,56,68.”

    From Membrane recruitment of the polarity protein Scribble by the cell adhesion receptor TMIGD1 (2023) · cites this paper as [18]

    The Results section on SCRIB mislocalization and Akt reports experiments in MCF-10A cells expressing hSCRIBP305L, but does not report c-Myc-induced apoptosis. The Discussion mentions cell death in connection with prior work on SCRIB loss, not a test of whether ectopic hSCRIBP305L suppresses c-Myc-induced apoptosis. Searches for c-Myc, Myc-induced cell death, and apoptosis did not locate that finding in our copy; page numbers were unavailable. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

1 of the 49 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Feigin, M. E., Akshinthala, S. D., Araki, K., Rosenberg, A. Z., Muthuswamy, L. B., Martin, B., Lehmann, B. D., Berman, H. K., Pietenpol, J. A., Cardiff, R. D., & Muthuswamy, S. K.
Affiliations
Ontario Institute for Cancer Research (CA)
Corresponding author
Muthuswamy, Senthil K.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-05-29
Volume
74
Issue
11
Pages
3180-3194
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-13-3415
PMC
PMC4096808
OpenAlex
W2107089643
Cited by
135
References
49
Citations by year
2026: 8 · 2025: 8 · 2024: 5 · 2023: 11 · 2022: 15 · 2021: 6 · 2020: 9 · 2019: 14 · 2018: 11 · 2017: 16 · 2016: 16 · 2015: 11 · 2014: 4
FWCI
6.43
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Cancer Institute (CA105388, U01CA105388, CA098830, R56CA098830, P30CA093373, R01CA098830)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
Keywords
Scribble, SCRIB, breast cancer, basal-like breast cancer, cell polarity, cell-cell contact, protein mislocalization, PTEN, PI3K signaling, mammary carcinogenesis, tumor suppressor, epithelial differentiation, transgenic mice
MeSH terms
Animals, Breast Neoplasms, Cell Line, Female, Humans, Membrane Proteins, Mice, Transgenic, Signal Transduction, Gene Expression, Cell Polarity, Phosphatidylinositol 3-Kinases, Tumor Suppressor Proteins, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, HEK293 Cells, Class I Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Carcinogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-30.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-30.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review