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


METHODS
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.
Department of Oncology, Georgetown University, Washington, District of Columbia.
Xiyuan
X
Zhang
Department of Surgical Sciences, Wake Forest University, Winston-Salem, North Carolina.
Katherine L
KL
Cook
Department of Oncology, Georgetown University, Washington, District of Columbia.|Institute of Biomedicine, University of Turku Medical Faculty, Turku, Finland.
Anni
A
Warri
Department of Oncology, Georgetown University, Washington, District of Columbia.
Idalia M
IM
Cruz
Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
Mariana
M
Rosim
Department of Oncology, Georgetown University, Washington, District of Columbia.
Jeffrey
J
Riskin
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois.
William
W
Helferich
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas.
Daniel
D
Doerge
Department of Oncology, Georgetown University, Washington, District of Columbia.
Robert
R
Clarke
Department of Oncology, Georgetown University, Washington, District of Columbia. clarkel@georgetown.edu.
Leena
L
Hilakivi-Clarke
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000097:blood; D004032:Diet; D000091342:Endoplasmic Reticulum Chaperone BiP; D020847:Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007529:Isoflavones / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D048789:Phytoestrogens / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D045730:Soy Foods / Q000009:adverse effects; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics
D018931:Antineoplastic Agents, Hormonal; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; D020847:Estrogen Receptor Modulators; C000717247:HSPA5 protein, human; D007529:Isoflavones; D048789:Phytoestrogens; D013629:Tamoxifen; D015127:9,10-Dimethyl-1,2-benzanthracene; D019833:Genistein