Abstract 4298: In-utero, but not pubertal, soy exposure suppresses estrogen-regulated gene expression in non-human primate breast

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Cynomolgus macaques (nonhuman primates, NHP) are highly similar to humans in their genetics, reproductive physiology, and anatomy. More importantly, they undergo a similar mammary gland development process and develop spontaneous breast cancers. Epidemiological studies of humans show that high soy intake is associated with lower breast cancer risk. Since nutrition and/or environmental exposure during youth are critical factors to disease risk in adulthood, timing of intervention may determine soy protective effect to breast cancer. Studies in NHP allow interrogation of developmental effects on the primate breast to a degree not possible in human subjects. We report here novel in-utero developmental effects of soy isoflavones (IF) on the NHP breast. Method: Soy IF were detected in amniotic fluid (255.5 + 93.3 nM) and milk (266.3 nM), which confirmed that soy exposure occurred in-utero and via nursing. We assessed the effects of in-utero and pre-pubertal soy exposure on the breast of NHP during puberty with a focus on changes related to estrogen exposure. We utilized mammary tissues from animals that were exposed to soy beginning in-utero (n=5 for soy and casein/control groups) or before puberty (n=12-17 for soy and casein groups). Animals were fed a diet modeled on a typical North American diet (35% calories from fat) with soy dose approximated at 120-180 mg IF/person/day. We assessed nipple length, mammary gland morphology, markers of mammary gland differentiation, proliferation, and estrogen receptor activity, and concentrations of serum estradiol and progesterone. Results: Regardless of dietary treatment, gene expression of estrogen-responsive markers in the breast was highest during pre-puberty and decreased across the pubertal transition (P<0.0001 for time effect on ESR1, PGR, GREB1, and TFF1). This pattern coincided with a decrease of terminal end bud structures and an increase of lobular differentiation and glandular area. Although an effect of dietary soy was not observed in pre-pubertally exposed animals, in-utero exposed animals showed lower expression of TFF1 (0.03-fold; P<0.05), a classic marker of estrogen receptor alpha (ER) activity. Serum estradiol level was not different with dietary treatment, nor did IF alter mRNA expression of estrogen-metabolizing enzymes in the breast. Conclusions and Future Directions: Our data suggest that timing of exposure may influence the effects of dietary soy on the breast; in-utero soy exposure resulted in modestly lower expression of a gene marker of ER activity, while pre-pubertal exposure had negligible effects on mammary gland outcomes. A follow-up study is currently underway to further examine potential effects of in-utero soy exposure on estrogen responsiveness and pubertal development, and whether epigenetic modulation is the underlying mechanism behind the differential expression of estrogen-related genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4298. doi:1538-7445.AM2012-4298