Early life exposure to soy affects breast cancer susceptibility through regulation of ER and cytokines
Introduction. Breast cancer is the most common non-cutaneous cancer in women in the US. Studies have found significant differences in the microbial composition between breast cancer patients and non-breast cancer patients.1 The diet affects breast cancer risk through multiple mechanisms, including estrogen and cytokines. Estrogens influence mammary gland development during puberty and breast cancer risk during adulthood. Early life diet exposure may alter estrogen levels, thus altering these processes.1 Asian women consume an average of 20–50 times more soy products per capita than western women and are less susceptible to developing breast cancer, making this compound a target of study.2 Soy foods contain isoflavones, which resemble estrogen and are able to act as estrogen receptor modulators.2 Genistein (GE) is an isoflavone that is shown to inhibit estrogen receptor α (ERα) and ERβ if given at high levels. GE has been shown to have anticancer properties in ERα-positive breast cancer cells.2 However, because isoflavones have different effects on different breast cancer cell lines, the use of soy as a breast cancer preventative remains controversial. Methods. Mammary gland samples were obtained from Cynomolgus Macaques during pubertal development, that were fed diets containing either casein or soy protein for ~4.5 years spanning menarche. Mammary tumors were induced in rats. Then, a group of control diet fed rats were switched to a GE diet. When the first tumor in a rat reached 1.4 cm in diameter, TAM was added to the diet, and a subset of previously only control diet fed rats also started GE intake (post-diagnosis GE). Estrogen-dependent MCF-7 cells and estrogen independent MDA-MB-231 cells were exposed to genistein (GE) and daidzein (DA). Results analyzed using a glass slide, multiplex sandwich ELISA based platform. Results. There is greater ER expression and activity during the pubertal transition, which decreases throughout menarche despite diet. ESR1 mRNA levels were lower post-menarche for monkeys that were fed soy. Pubertal consumption of isoflavones increased responsiveness to TAM in ER + breast cancer cells by downregulating the UPR pathway. Isoflavones decrease levels of cytokines CXCL16 and VEGF, two promoters of angiogenesis and metastasis in breast cancer. However, isoflavones are shown to have contradicting effects in two different types of breast cancer cells. In MCF-7 estrogen-dependent cells, isoflavones induced a biphasic effect: stimulating cell growth at relatively low concentrations and causing inhibition at higher concentrations. In MDA-MB-231 cancer cells, isoflavones were only shown to have an inhibitory effect. Discussion. There is greater ER expression and activity during the pubertal transition, supporting the idea that this life stage is a critical window for phenotypic modulation by estrogenic compounds. Isoflavones are able to act as estrogen modulators and play a key role in breast cancer susceptibility. Intake of soy during puberty is shown to be the most beneficial. Increased inhibition in the MDA-MB hormone independent line, reveals that isoflavones act through other mechanisms besides estrogen. More research must be done to determine the safety of genistein consumption for ER+ breast cancer patients.
- Dewi FN, Wood CE, Willson CJ, et al. Effects of Pubertal Exposure to Dietary Soy on Estrogen Receptor Activity in the Breast of Cynomolgus Macaques. Cancer Prevention Research. 2016;9(5):385-395. doi:10.1158/1940-6207.capr-15-0165.
- Paul, Bidisha, et al. “Impact of Genistein on the Gut Microbiome of Humanized Mice and Its Role in Breast Tumor Inhibition.” Plos One, vol. 12, no. 12, 2017, doi:10.1371/journal.pone.0189756.
- Zhang, Xiyuan, et al. “Lifetime Genistein Intake Increases the Response of Mammary Tumors to Tamoxifen in Rats.” Clinical Cancer Research, vol. 23, no. 3, 2017, pp. 814–824., doi:10.1158/1078-0432.ccr-16-1735.
- Uifalean, Alina, et al. “Influence of Soy Isoflavones in Breast Cancer Angiogenesis: a Multiplex Glass ELISA Approach.” Journal of B.U.ON. : Official Journal of the Balkan Union of Oncology, U.S. National Library of Medicine, Dec. 2018, www.ncbi.nlm.nih.gov/pubmed/30722112.
- Xiao, Gang, et al. “CXCL16/CXCR6 Chemokine Signaling Mediates Breast Cancer Progression by pERK1/2-Dependent Mechanisms.” Oncotarget, vol. 6, no. 16, 2015, doi:10.18632/oncotarget.3690.