Impact of Short-term Calorie Restriction on HER2-Overexpressing Breast Cancer

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  • February 26, 2019
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  • Rainey, Magdalena
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Background: Among American women, 30% of all new cancer diagnoses are of breast cancer (BC) and ~25% of these cancers overproduce the growth-promoting tyrosine kinase receptor, HER2. Although there are targeted treatments available for HER2-overexpressing BC, this disease is associated with poorer prognosis and increased risk of recurrence, making identification of new treatment methods crucial. It is well-established that calorie restriction (CR), or chronic dietary energy restriction by ~30%, has significant tumor suppressive effects across cancer subtypes and has potential to be utilized as an adjunctive therapy. This study investigates the mechanisms by which CR decreases HER2-overexpressing BC progression.Methods: To mimic CR in vitro, murine MMTV-neu cells that overexpress HER2 were treated with medias containing reduced serum (1%), reduced glucose (1mM), or reduced serum and reduced glucose (1%/1mM) compared to control media (10% serum, 25mM glucose). The impact of differential nutrient restriction on MMTV-neu regulatory mechanisms was characterized using MTT assays, anchorage independent colony formation assays, cell cycle analysis, and apoptosis assays. To investigate the mechanism of this alteration, western blotting analysis of proteins along the PI3K/Akt and Ras/Erk pathways was conducted. The efficacy of nutrient restriction as an adjunct therapy was explored by treating cells cultured in restricted medias with lapatinib, doxorubicin, and cyclophosphamide.Results: Serum restriction significantly reduced cellular viability and colony formation of MMTV-neu cells and promoted increased cellular apoptosis, and G0/G1 cell cycle arrest. In MMTV-neu cells treated with serum restricted medias (1% and 1%/1mM), there was a significant decrease in activity of tumor-suppressor protein p21. Both p21 and phospho-21 expression was decreased with serum restriction, as well as the proportion of phospho-p21 relative to p21 (p<0.05). Serum and glucose restriction (1%/1mM) increased the sensitivity of MMTV-neu cells to treatment with lapatinib and cyclophosphamide, resulting in reduced cellular viability (p<0.05).Conclusion: These results suggest that short-term CR, achieved specifically through serum restriction alone or in combination with glucose restriction, is associated with decreased phosphorylation and cytoplasmic localization of p21, which may be responsible for modulating anti-proliferative activities. This finding is significant because clinical studies have found that increased cytoplasmic p21 in HER2-overexpressing BC predicted reduced survival in patients at 5 years. Utilizing CR in conjunction with existing therapies may prevent or reverse cytoplasmic p21 localization in this cancer subtype, highlighting the importance of this investigation.
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  • In Copyright
Advisor
  • Hursting, Stephen
Degree
  • Bachelor of Science in Public Health
Honors level
  • Honors
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2018
Language
  • English

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