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

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.

Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

“…These mechanisms support our finding with less PR-positivity in the carbohydrate arm. All together, these components of the endocrine switch make CTCs more resilient to the adjuvant endocrine treatment that follows surgery [9,54]. The present study seems to support the novel principle of manipulation of the perioperative nutrient status for adjuvant treatment purposes.…”

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

“…[42,43], suggesting that pretreatment insulin levels might have a prognostic role not only in early BC but also in advanced stages of disease, thus reinforcing the rationale for lifestyle or insulintargeting pharmacologic interventions as a means of improving breast cancer outcomes. In this light, it is worth mentioning an in vitro studyon BC cells showing how insulin priming potentially contributes to the estradiol-induced cancer growth by modulating estradiol-insulin signaling crosstalk [46].…”

Obesity and Cancer: An Angiogenic and Inflammatory Link

“…One such agent, currently under intense clinical investigation, is metformin, the most widely prescribed anti-diabetic generic drug that is also frequently administered to diabetic PDAC patients [47]. Metformin can improve treatment outcomes in preclinical models of cancer, particularly in the obese setting [1,3,58,86,112,118,127,152,164,170,178,181]. In addition, it reduces the incidence of cancer in diabetic patients as well as improves survival in newly diagnosed cases [28,94,97,102,144,152].…”