한국콩연구회

Soy and Breast Cancer: Point-Counterpoint

By Mark Messina, PhD

The relationship between soy intake and breast cancer, which has been rigorously investigated for more than two decades, is controversial as there exists evidence suggesting soyfoods may both increase and decrease risk. Initial interest in this area of research1 was fueled by the historically low breast cancer incidence rates in soyfood-consuming countries, especially Japan,2and animal data showing that adding soybean isoflavones to the diets of laboratory rats inhibited chemically-induced mammary cancer.3 Recent evidence suggests that to derive protection against breast cancer, soy needs to be consumed during childhood and/or adolescence.4-5 Although isoflavone exposure early in life may reduce breast cancer risk, one widely used mouse model shows that isoflavones can stimulate the growth of existing estrogen-sensitive mammary tumors.6Conversely, however, recent epidemiologic data show post-diagnosis soy consumption improves the prognosis of breast cancer patients.7, 8 The point-counterpoint below highlights the most relevant data related to the issue of soy consumption by breast cancer patients and women at high risk of developing breast cancer.

Point ▶ Estrogen increases breast cancer risk therefore isoflavones increase risk because they are phytoestrogens.9 Soyfoods increase breast cancer risk because they are uniquely rich sources of isoflavones.10

◀ Counterpoint Isoflavones are phytoestrogens but they are also classified as selective estrogen receptor modulators (SERMs).11SERMs, which include the breast cancer drug tamoxifen, can have effects similar to and opposite to those of estrogen or no effects at all in tissues that are affected by estrogen.

The effect of estrogen therapy on breast cancer risk is unclear. In the Women’s Health Initiative trial, the largest trial of its kind, estrogen therapy actually decreased risk.12 In epidemiologic studies, estrogen use is associated with a very modest increase in risk.13 According to a recent commentary in the Journal of the National Cancer Institute by Chlebowski and Anderson “ . . . the effect of estrogen-only formulation use on breast cancer risk in postmenopausal women, even with longer-term hormone use, still stands unanswered.”14

Point ▶ Genistein (the primary soy isoflavone) increases the growth of estrogen-sensitive human breast cancer cells (MCF-7) in vitro15 and stimulates the growth of mammary tumors in athymic (lacking an immune system) ovariectomized (lacking ovaries) mice implanted with these cells.15

◀ Counterpoint In vitro results often poorly predict in vivo effects.16 Athymic mice metabolize isoflavones much differently than humans so their value for understanding the effects of soyfoods in humans is unclear.17, 18

Recent research failed to find that genistein stimulated mammary tumor growth in athymic ovariectomized mice.19 (The estrogen concentration of the media in which the MCF-7 cells are placed prior to implantation determines how they are affected by genistein in vivo).

Point ▶ In athymic ovariectomized mice implanted with MCF-7 cells, genistein inhibits the efficacy of tamoxifen20 and the aromatase inhibitor letrozole.21

◀ Counterpoint In epidemiologic studies from China7, 22 and the United States,8, 23 post-diagnosis soy intake improves the prognosis (reduces recurrence and improves survival) of breast cancer patients, has no impact on the efficacy of tamoxifen7, 8, 23 and in the one study to examine this relationship, enhanced the efficacy of the aromatase inhibitor, anastrozole.22

Point ▶ Clinical studies show hormone therapy (estrogen plus progestin) increases markers of breast cancer risk (breast tissue density24 and breast cell proliferation25, 26) and increases breast cancer risk.27

◀ Counterpoint Clinical studies show neither soyfoods nor isoflavone supplements affect markers of breast cancer risk including breast tissue density and breast cell proliferation.28

REFERENCES

1. Messina M, Barnes S. The role of soy products in reducing risk of cancer. J Natl Cancer Inst. 1991; 83: 541-6.

2. Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer. 1999; 83: 18-29.

3. Barnes S, Grubbs C, Setchell KD, Carlson J. Soybeans inhibit mammary tumors in models of breast cancer. Prog Clin Biol Res. 1990; 347:: 239-53.

4. Messina M, Hilakivi-Clarke L. Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Nutr Cancer. 2009; 61: 792-798.

5. Messina M, Wu AH. Perspectives on the soy-breast cancer relation. Am J Clin Nutr. 2009; 89: 1673S-1679S.

6. Helferich WG, Andrade JE, Hoagland MS. Phytoestrogens and breast cancer: a complex story. Inflammopharmacology. 2008; 16: 219-26.

7. Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. JAMA. 2009; 302: 2437-43.

8. Caan BJ, Natarajan L, Parker B, Gold EB, Thomson C, Newman V, Rock CL, Pu M, Al-Delaimy W, et al. Soy food consumption and breast cancer prognosis. Cancer Epidemiol Biomarkers Prev. 2011; 20: 854-8.

9. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998; 139: 4252-63.

10. Franke AA, Custer LJ, Wang W, Shi CY. HPLC analysis of isoflavonoids and other phenolic agents from foods and from human fluids. Proc Soc Exp Biol Med. 1998; 217: 263-73.

11. Oseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med. 2008; 74: 1656-65.

12. Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006; 295: 1647-57.

13. Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 2005; 11: 545-60.

14. Chlebowski RT, Anderson GL. The influence of time from menopause and ammography on hormone therapy-related breast cancer risk assessment. J Natl Cancer Inst. 2011; 103: 1-2.

15. Hsieh CY, Santell RC, Haslam SZ, Helferich WG. Estrogenic effects of genistein on the growth of estrogen receptor- positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res. 1998; 58: 3833-8.

16. Radiloff DR, Rinella ES, Threadgill DW. Modeling cancer patient populations in mice: complex genetic and environmental factors. Drug discovery today Disease models. 2008; 4: 83-88.

17. Gu L, House SE, Prior RL, Fang N, Ronis MJ, Clarkson TB, Wilson ME, Badger TM. Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women. J Nutr. 2006; 136: 1215-21.

18. Setchell KD, Brown NM, Zhao X, Lindley SL, Heubi JE, King EC, Messina MJ. Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. Am J Clin Nutr. 2011; 94: 1284-94.

19. Onoda A, Ueno T, Uchiyama S, Hayashi SI, Kato K, Wake N. Effects of S-equol and natural S-equol supplement (SE5-OH) on the growth of MCF-7 in vitro and as tumors implanted into ovariectomized athymic mice. Food Chem Toxicol. 2011.

20. Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG. Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res. 2002; 62: 2474-7.

21. Ju YH, Doerge DR, Woodling KA, Hartman JA, Kwak J, Helferich WG. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis. 2008; 29: 2162-8.

22. Kang X, Zhang Q, Wang S, Huang X, Jin S. Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. CMAJ. 2010; 182: 1857-62.

23. Guha N, Kwan ML, Quesenberry CP, Jr., Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009; 118: 395-405.

24. Martin LJ, Minkin S, Boyd NF. Hormone therapy, mammographic density, and breast cancer risk. Maturitas. 2009; 64: 20-6.

25. Conner P, Skoog L, Soderqvist G. Breast epithelial proliferation in postmenopausal women evaluated through fine-needle-aspiration cytology. Climacteric. 2001; 4: 7-12.

26. Conner P, Soderqvist G, Skoog L, Graser T, Walter F, Tani E, Carlstrom K, von Schoultz B. Breast cell proliferation in postmenopausal women during HRT evaluated through fine needle aspiration cytology. Breast Cancer Res Treat. 2003; 78: 159-65.

27. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288: 321-33.

28. Messina MJ, Wood CE. Soy isoflavones, estrogen therapy, and breast cancer risk: Analysis and commentary. Nutr J. 2008; 7: 17.

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