Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization

Partanen, Juhaní; Nieminen, Anni I.; Mäkelä, Tomi P.; Klefström, Juha

doi:10.1073/pnas.0704677104

Cited by 96 publications

(113 citation statements)

References 27 publications

(36 reference statements)

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“…2A). 33 To test whether MYC-induced apoptosis correlates with disturbed lineage-identity under these culture conditions, we treated developing MCF10A acini with 4-OHT. In 2D monolayer culture, more than 80 % of MCF10A cells stain positive for the basal Keratin 14 (K14), while the remaining cells are Keratin 8 (K8, luminal) or double positive.…”

Section: Resultsmentioning

confidence: 99%

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MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesiondependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.

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Section: Resultsmentioning

confidence: 99%

“…7,33 Stable overexpression of MYC or MYC-ER fusion proteins was achieved by transduction with lentiviral pRRL-SFFV vectors and packaging plasmids psPAX2 and pMD2.G (Didier Trono) in the presence of 8 mg/ml protamine sulfate.…”

Section: Methodsmentioning

confidence: 99%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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“…The detailed procedure was previously described ( 46 ) and is provided in the Supplementary Methods.…”

Section: D Culturementioning

confidence: 99%

Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2

et al. 2015

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Regulatory pathways that drive early hematogenous dissemination of tumor cells are insuffi ciently defi ned. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to defi ne patients with early disseminated breast cancer and identifi ed low retinoic acid-induced 2 (RAI2) expression to be signifi cantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERα, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells. SIGNIFICANCE:We identifi ed downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors. We specifi ed the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer. Cancer Discov;5(5);

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“…One study-using mammary epithelial cells grown in a 3-dimensional Matrigel culture system-has shown that polarity defects accompanying LKB1 inactivation unmask the oncogenic activity of c-Myc (Partanen et al, 2007). In this system, proliferating cells eventually form into quiescent polarized acinar structures.…”

Section: Mechanisms Of Polarity Controlmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization

Abstract: 3D culture ͉ apoptosis

Cited by 96 publications

References 27 publications

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2

LKB1; linking cell structure and tumor suppression

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