Lifetime Genistein Intake Increases the Response of Mammary Tumors to Tamoxifen in Rats

Clin Cancer Res. 2017 Feb 1;23(3):814-824. doi: 10.1158/1078-0432.CCR-16-1735.

Abstract

Purpose: Whether it is safe for estrogen receptor-positive (ER+) patients with breast cancer to consume soy isoflavone genistein remains controversial. We compared the effects of genistein intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen therapy using a preclinical model.

Experimental design: Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm genistein from postnatal day 15 onward (lifetime genistein). Mammary tumors were induced with 7,12-dimethylbenz(a)anthracene (DMBA), after which a group of control diet-fed rats were switched to genistein diet (adult genistein). When the first tumor in a rat reached 1.4 cm in diameter, tamoxifen was added to the diet and a subset of previously only control diet-fed rats also started genistein intake (post-diagnosis genistein).

Results: Lifetime genistein intake reduced de novo resistance to tamoxifen, compared with post-diagnosis genistein groups. Risk of recurrence was lower both in the lifetime and in the adult genistein groups than in the post-diagnosis genistein group. We observed downregulation of unfolded protein response (UPR) and autophagy-related genes (GRP78, IRE1α, ATF4, and Beclin-1) and genes linked to immunosuppression (TGFβ and Foxp3) and upregulation of cytotoxic T-cell marker CD8a in the tumors of the lifetime genistein group, compared with controls, post-diagnosis, and/or adult genistein groups.

Conclusions: Genistein intake mimicking Asian consumption patterns improved response of mammary tumors to tamoxifen therapy, and this effect was linked to reduced activity of UPR and prosurvival autophagy signaling and increased antitumor immunity. Clin Cancer Res; 23(3); 814-24. ©2017 AACR.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Autophagy / drug effects
  • Autophagy / genetics
  • Cytokines / blood
  • Diet
  • Estrogen Receptor Modulators / pharmacology
  • Estrogen Receptor Modulators / therapeutic use*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genistein / administration & dosage
  • Genistein / blood
  • Genistein / pharmacology*
  • Isoflavones / blood
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / pathology
  • Phytoestrogens / administration & dosage
  • Phytoestrogens / blood
  • Phytoestrogens / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Recurrence
  • Soy Foods* / adverse effects
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use*
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / genetics

Substances

  • Antineoplastic Agents, Hormonal
  • Cytokines
  • Estrogen Receptor Modulators
  • Isoflavones
  • Phytoestrogens
  • Tamoxifen
  • 9,10-Dimethyl-1,2-benzanthracene
  • Genistein