The Effects of Soy Supplementation on Gene Expression in Breast Cancer: A Randomized Placebo-controlled Study

Moshe Shike; Ashley S. Doane; Lianne Russo; Rafael Cabal; Jorge S. Reis-Filho; William Gerald; Hiram Cody; Raya Khanin; Jacqueline Bromberg; Larry Norton

Disclosures

J Natl Cancer Inst. 2014;106(9) 

In This Article

Abstract and Introduction

Abstract

Background There are conflicting reports on the impact of soy on breast carcinogenesis. This study examines the effects of soy supplementation on breast cancer-related genes and pathways.

Methods Women (n = 140) with early-stage breast cancer were randomly assigned to soy protein supplementation (n = 70) or placebo (n = 70) for 7 to 30 days, from diagnosis until surgery. Adherence was determined by plasma isoflavones: genistein and daidzein. Gene expression changes were evaluated by NanoString in pre- and posttreatment tumor tissue. Genome-wide expression analysis was performed on posttreatment tissue. Proliferation (Ki67) and apoptosis (Cas3) were assessed by immunohistochemistry.

Results Plasma isoflavones rose in the soy group (two-sided Wilcoxon rank-sum test, P < .001) and did not change in the placebo group. In paired analysis of pre- and posttreatment samples, 21 genes (out of 202) showed altered expression (two-sided Student's t-test, P < .05). Several genes including FANCC and UGT2A1 revealed different magnitude and direction of expression changes between the two groups (two-sided Student's t-test, P < .05). A high-genistein signature consisting of 126 differentially expressed genes was identified from microarray analysis of tumors. This signature was characterized by overexpression (>2-fold) of cell cycle transcripts, including those that promote cell proliferation, such as FGFR2, E2F5, BUB1, CCNB2, MYBL2, CDK1, and CDC20 (P < .01). Soy intake did not result in statistically significant changes in Ki67 or Cas3.

Conclusions Gene expression associated with soy intake and high plasma genistein defines a signature characterized by overexpression of FGFR2 and genes that drive cell cycle and proliferation pathways. These findings raise the concerns that in a subset of women soy could adversely affect gene expression in breast cancer.

Introduction

Many women consume soy in the belief that it prevents breast cancer, or treats the disease. This practice is based primarily on results of epidemiological studies, yet the impact of soy on breast cancer (BC) is not clearly understood. Soy can exert either pro- or antiestrogenic effects and may have other effects on cellular events. It is not clear if soy is protective or harmful in some circumstances.[1,2] The effect of soy intake on critical signaling molecules, cellular markers, and gene products associated with BC remains unknown. In prospective observational studies in Asian populations, soy intake was associated with reduced risk of BC incidence and recurrence.[3–5] When stratified by amount of soy consumed, a dose-response relationship has been reported with a statistically significant trend of decreasing risk with increasing soy food intake, translating to a 16% risk reduction per 10mg of daily isoflavone consumed.[4] Yet soy intake was unrelated to BC risk in multiple prospective studies in western populations, and patients with BC are frequently advised to avoid soy foods.[4,6] The tumorigenic properties of soy isoflavones are well documented in BC cell lines, and animal models and are largely associated with their estrogenic properties.[1,2,7]

Soybeans contain the isoflavones genistein and daidzein. Genistein stimulates growth of estrogen-sensitive BC cells through transactivation of the estrogen receptor (ER), and can block the inhibitory effects of tamoxifen.[7–9] However, isoflavones have also been reported to decrease BC cell growth through ER-independent inhibition of tyrosine kinases and DNA topoisomerases.[10–15] Additionally, genistein exerts anti-inflammatory and anti-angiogenic effects through the regulation of VEGF and VEGFR-2 expression.[16–18]

Human intervention studies have not led to conclusive results regarding soy effects on biomarkers of mammary tumorigenesis. Gene expression profiling using microarray technologies has provided critical insights into the molecular classification of BC, improved our understanding of BC biology, and generated clinically useful information about prognosis and response to therapy.[19] Given the presumed importance of soy in modulating BC risk, we aimed to identify its effects on the expression of genes and pathways in BC.

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