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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

Loss of tumor suppressor Merlin in advanced breast cancer is due to post-translational regulation

K Adam Morrow1, Shamik Das, Brandon J Metge

  • 1Department of Oncologic Sciences, Mitchell Cancer Institute, Mobile, Alabama 36604, USA.

The Journal of Biological Chemistry
|October 4, 2011
PubMed

Insights

Merlin, a tumor suppressor, is decreased in breast cancer due to osteopontin (OPN). Restoring Merlin reduced tumor growth and malignancy. A model using Merlin and OPN shows diagnostic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The tumor suppressor Merlin's role in breast cancer remains uninvestigated, unlike in nervous system malignancies.
  • No Merlin mutations have been identified in breast cancer, necessitating research into its expression and function.

Purpose of the Study:

  • To investigate the expression and role of the tumor suppressor Merlin in breast cancer.
  • To elucidate the mechanism behind Merlin downregulation in breast cancer.
  • To develop a diagnostic model based on Merlin and osteopontin (OPN) expression.

Main Methods:

  • Immunohistochemistry and real-time PCR were used to assess Merlin expression in breast cancer tissues.
  • Osteopontin (OPN) and Akt-mediated phosphorylation were investigated as mechanisms for Merlin degradation.
  • Functional assays and xenograft tumor models were employed to evaluate the impact of Merlin restoration.
  • Logistic regression modeling was used to develop a diagnostic model based on Merlin and OPN expression.

Main Results:

  • Merlin protein expression was significantly decreased in breast cancer tissues, despite comparable transcript levels.
  • Increased osteopontin (OPN) expression correlated with decreased Merlin levels, mediated by OPN-initiated Akt-dependent phosphorylation and proteasomal degradation of Merlin.
  • Restoring Merlin expression reduced breast cancer cell invasion, migration, motility, and impeded tumor xenograft growth.
  • A logistic regression model utilizing Merlin and OPN expression demonstrated consistent discrimination of breast tumor tissues.

Conclusions:

  • Merlin acts as a suppressor of breast malignancy, with its loss being a key event in breast cancer progression.
  • Osteopontin (OPN) plays a critical role in the downregulation of Merlin protein in breast cancer via Akt-mediated phosphorylation and degradation.
  • A novel diagnostic model based on Merlin and OPN expression shows promise for identifying breast tumor tissues.

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