Insulin priming effect on estradiol-induced breast cancer metabolism and growth

Peninah M. Wairagu, Ai N.H. Phan, Min Kyu Kim, Jeongwoo Han, Hyun Won Kim, Jong Whan Choi, Ki Woo Kim, Seung Kuy Cha, Kwang Hwa Park, Yangsik Jeong

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11 Citations (Scopus)

Abstract

Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes.

Original languageEnglish
Pages (from-to)484-492
Number of pages9
JournalCancer Biology and Therapy
Volume16
Issue number3
DOIs
Publication statusPublished - 2015 Mar 1

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Wairagu, P. M., Phan, A. N. H., Kim, M. K., Han, J., Kim, H. W., Choi, J. W., Kim, K. W., Cha, S. K., Park, K. H., & Jeong, Y. (2015). Insulin priming effect on estradiol-induced breast cancer metabolism and growth. Cancer Biology and Therapy, 16(3), 484-492. https://doi.org/10.1080/15384047.2015.1016660