Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model

Camila Leonel, Thaiz Ferraz Borin, Lívia de Carvalho Ferreira, Marina Gobbe Moschetta, Marcio Chaim Bajgelman, Alicia M. Viloria-Petit, Debora Aparecida Pires de Campos Zuccari

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Epithelial mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties, generating metastases. Transforming growth factor beta (TGF-β) is associated with this malignancy by having the ability to induce EMT. Metformin, has been shown to inhibit EMT in breast cancer cells. Based on this evidence we hypothesize that treatment with metformin and the silencing of TGF-β, inhibits the EMT in cancer cells. Canine metastatic mammary tumor cell line CF41 was stably transduced with a shRNA-lentivirus, reducing expression level of TGF-β1. This was combined with metformin treatment, to look at effects on cell migration and the expression of EMT markers. For in vivo study, unmodified or TGF-β1sh cells were injected in the inguinal region of nude athymic female mice followed by metformin treatment. The mice’s lungs were collected and metastatic nodules were subsequently assessed for EMT markers expression. The migration rate was lower in TGF-β1sh cells and when combined with metformin treatment. Metformin treatment reduced N-cadherin and increased E-cadherin expression in both CF41 and TGF-β1sh cells. Was demonstrated that metformin treatment reduced the number of lung metastases in animals bearing TGF-β1sh tumors. This paralleled a decreased N-cadherin and vimentin expression, and increased E-cadherin and claudin-7 expression in lung metastases. This study confirms the benefits of TGF-β1 silencing in addition to metformin as potential therapeutic agents for breast cancer patients, by blocking EMT process. To the best of our knowledge, we are the first to report metformin treatment in cells with TGF-β1 silencing and their effect on EMT.

Original languageEnglish (US)
Pages (from-to)27-41
Number of pages15
JournalJournal of Mammary Gland Biology and Neoplasia
Volume22
Issue number1
DOIs
StatePublished - Mar 1 2017

Fingerprint

Epithelial-Mesenchymal Transition
Metformin
Heterografts
Transforming Growth Factor beta
Canidae
Breast Neoplasms
Neoplasm Metastasis
Cadherins
Therapeutics
Nude Mice
Lung
Neoplasms
Lentivirus
Groin
Vimentin
Tumor Cell Line
Small Interfering RNA
Cell Movement
Epithelial Cells

Keywords

  • Anticarcinogenic agents
  • Breast cancer
  • Metastasis
  • TGF-β
  • shRNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model. / Leonel, Camila; Borin, Thaiz Ferraz; de Carvalho Ferreira, Lívia; Moschetta, Marina Gobbe; Bajgelman, Marcio Chaim; Viloria-Petit, Alicia M.; de Campos Zuccari, Debora Aparecida Pires.

In: Journal of Mammary Gland Biology and Neoplasia, Vol. 22, No. 1, 01.03.2017, p. 27-41.

Research output: Contribution to journalArticle

Leonel, Camila ; Borin, Thaiz Ferraz ; de Carvalho Ferreira, Lívia ; Moschetta, Marina Gobbe ; Bajgelman, Marcio Chaim ; Viloria-Petit, Alicia M. ; de Campos Zuccari, Debora Aparecida Pires. / Inhibition of Epithelial-Mesenchymal Transition and Metastasis by Combined TGFbeta Knockdown and Metformin Treatment in a Canine Mammary Cancer Xenograft Model. In: Journal of Mammary Gland Biology and Neoplasia. 2017 ; Vol. 22, No. 1. pp. 27-41.
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AU - Bajgelman, Marcio Chaim

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