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CCN6 Suppresses Metaplastic Breast Carcinoma by Antagonizing Wnt/ß-Catenin Signaling to Inhibit EZH2-Driven EMT.
Gonzalez, Maria E; Brophy, Bryce; Eido, Ahmad; Leonetti, Adele E; Djomehri, Sabra I; Augimeri, Giuseppina; Carruthers, Nicholas J; Cavalcante, Raymond G; Giordano, Francesca; Andò, Sebastiano; Nesvizhskii, Alexey I; Fearon, Eric R; Kleer, Celina G.
Afiliación
  • Gonzalez ME; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
  • Brophy B; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
  • Eido A; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
  • Leonetti AE; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
  • Djomehri SI; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
  • Augimeri G; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
  • Carruthers NJ; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
  • Cavalcante RG; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
  • Giordano F; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
  • Andò S; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
  • Nesvizhskii AI; Bioinformatics Core, University of Michigan, Ann Arbor, Michigan.
  • Fearon ER; Bioinformatics Core, University of Michigan, Ann Arbor, Michigan.
  • Kleer CG; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
Cancer Res ; 84(19): 3235-3249, 2024 Oct 01.
Article en En | MEDLINE | ID: mdl-39024552
ABSTRACT
Metaplastic breast carcinomas (mBrCA) are a highly aggressive subtype of triple-negative breast cancer with histologic evidence of epithelial-to-mesenchymal transition and aberrant differentiation. Inactivation of the tumor suppressor gene cellular communication network factor 6 (CCN6; also known as Wnt1-induced secreted protein 3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with epithelial-to-mesenchymal transition. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. In this study, we showed that CCN6 interacts with the Wnt receptor FZD8 and coreceptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of ß-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a ß-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/ß-catenin/TCF signaling in Ccn6-KO mBrCA cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacologic inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated ß-catenin and high EZH2 in human spindle mBrCAs compared with other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a ß-catenin/TCF/EZH2 axis and highlight the inhibition of ß-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs.

Significance:

CCN6 deficiency drives metaplastic breast carcinoma growth and metastasis by increasing Wnt/ß-catenin activation to upregulate EZH2, identifying EZH2 inhibition as a mechanistically guided treatment strategy for this deadly form of breast cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas CCN de Señalización Intercelular / Transición Epitelial-Mesenquimal / Vía de Señalización Wnt / Proteína Potenciadora del Homólogo Zeste 2 Límite: Animals / Female / Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas CCN de Señalización Intercelular / Transición Epitelial-Mesenquimal / Vía de Señalización Wnt / Proteína Potenciadora del Homólogo Zeste 2 Límite: Animals / Female / Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos