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Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections

Francesca Bianchi1, Elda Tagliabue, Sylvie Ménard

  • 1Fondazione IRCCS-Istituto Nazionale Tumori, Milan, Italy.

Cell Cycle (Georgetown, Tex.)
|March 22, 2007
PubMed

Insights

The tumor suppressor FHIT (Fragile Histidine Triad) plays a protective role in HER2-driven breast cancer. Loss of FHIT function correlates with HER2 overexpression, suggesting gene cooperation in carcinogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The tumor suppressor gene FHIT is frequently inactivated in human cancers.
  • FHIT protein levels are regulated by proteasome degradation, influenced by EGFR family members like HER2.
  • HER2 overexpression is a known poor prognostic factor in breast cancer.

Purpose of the Study:

  • To investigate the relationship between FHIT inactivation and HER2 overexpression in human breast carcinomas.
  • To determine the functional role of FHIT in HER2-driven mammary tumor development.

Main Methods:

  • Analysis of Fhit protein levels in 384 human primary breast carcinomas.
  • Assessment of mammary tumor incidence in a mouse model with inactivated Fhit alleles crossed with HER2-expressing mice.

Main Results:

  • Low or absent Fhit protein levels were more frequent in HER2-overexpressing breast tumors.
  • Mice with one inactivated Fhit allele developed mammary tumors more frequently than those with two functional alleles.
  • Presence of functional FHIT alleles reduced tumor incidence in the HER2-driven mouse model.

Conclusions:

  • FHIT exhibits a protective role against HER2-driven mammary tumorigenesis.
  • FHIT and HER2 cooperate in the process of breast carcinogenesis.
  • FHIT inactivation may contribute to the progression of HER2-positive breast cancers.

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