Fhit Nuclear Import Following EGF Stimulation Sustains Proliferation of Breast Cancer Cells
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Updated: Apr 17, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Francesca Bianchi1,2, Marianna Sasso1, Federica Turdo1
1Molecular Targeting Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Abstract:
The tumor-suppressor protein fragile histidine triad (Fhit) exerts its functions in the cytoplasm, although some reports suggest that it may also act in the nucleus. We previously showed that cytosolic Fhit protein levels in cancer cell lines stimulated to proliferate were reduced by proteasomal degradation. Here, we demonstrate that Fhit is physiologically present in the nucleus of breast cancer cell lines and tissues at a low level and that proliferative stimulation increases nuclear levels. Breast cancer cells expressing the FhitY114F mutant, which do not undergo proteasomal degradation, contained mutated Fhit in the nucleus, while cells treated with a proteasome inhibitor accumulated nuclear Fhit during proliferation. Thus, Fhit nuclear shuttling and proteasome degradation phenomena occur independently. When Fhit was coupled to a nuclear localization sequence, the proliferation rate of the transfected cells increased together with levels of proliferation pathway mediators cyclin D1, phospho-MAPK, and phospho-STAT3. Fhit nuclear translocation upon mitogenic stimulation may represent a new regulatory mechanism that allows rapid restoration of Fhit cytoplasmic levels and promotes the proliferation cascade activated by mitogenic stimulation.
Insights
The tumor suppressor protein fragile histidine triad (Fhit) is found in the nucleus of breast cancer cells. Proliferative stimulation increases nuclear Fhit, suggesting a role in cancer cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The tumor suppressor protein fragile histidine triad (Fhit) primarily functions in the cytoplasm.
- Previous research indicated cytosolic Fhit levels decrease with proteasomal degradation during cancer cell proliferation.
Purpose of the Study:
- To investigate the presence and role of Fhit in the nucleus of breast cancer cells.
- To elucidate the relationship between Fhit nuclear localization, proteasomal degradation, and cell proliferation.
Main Methods:
- Analysis of Fhit localization in breast cancer cell lines and tissues.
- Utilizing FhitY114F mutants and proteasome inhibitors to study Fhit degradation.
- Transfection experiments with Fhit coupled to a nuclear localization sequence.
Main Results:
- Fhit is physiologically present at low levels in the nucleus of breast cancer cells and tissues.
- Proliferative stimulation increases nuclear Fhit levels, independent of proteasomal degradation.
- Increased nuclear Fhit, via translocation or mutation, correlates with enhanced cell proliferation and elevated cyclin D1, phospho-MAPK, and phospho-STAT3.
Conclusions:
- Fhit undergoes nuclear translocation upon mitogenic stimulation in breast cancer.
- Nuclear Fhit shuttling and proteasomal degradation are independent processes.
- Nuclear Fhit translocation may be a mechanism to rapidly restore cytoplasmic levels and promote proliferation.
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