Email updates

Keep up to date with the latest news and content from Breast Cancer Research and BioMed Central.

Commentary

From Bittner to Barr: a viral, diet and hormone breast cancer aetiology hypothesis

James S Lawson1*, Dinh Tran2 and William D Rawlinson3

Author Affiliations

1 Center for Public Health, School of Health Services Management, University of New South Wales, Sydney, New South Wales, Australia

2 Anatomical Pathology, St Vincents Hospital, Darlinghurst, New South Wales, Australia

3 Division of Virology, Prince of Wales Hospital, Randwick, New South Wales, Australia

For all author emails, please log on.

Breast Cancer Res 2001, 3:81-85  doi:10.1186/bcr275


The electronic version of this article is the complete one and can be found online at:


Published:18 December 2000

© 2000 BioMed Central Ltd

Abstract

It is hypothesized that the human homologue of the mouse mammary tumour virus (HHMMTV) and other viruses, such as human papillomavirus (HPV) and Epstein-Barr virus (EBV), act as cofactors with diet, oestrogens and other hormones in the initiation and promotion of some types of breast cancer in genetically susceptible women. It is further hypothesized that diet influences the risk of breast cancer, through its influence on oestrogen metabolism and that of other hormones, in combination with genetic and infectious agents.

Keywords:
breast cancer; diet; Epstein-Barr virus; human papillomavirus; mouse mammary tumour virus; oestrogens

Introduction

In 1943, Bittner [1] demonstrated three cofactors in the development of spontaneous mammary tumours in mice. These were inherited susceptibility, hormonal influences, and a transmissible influence in mother's milk. This transmissible influence has since been shown to be a retrovirus, now known as the mouse mammary tumor virus (MMTV). This virus is oncogenic in the oestrogenic milieu of female mice of strains with a genetic susceptibility to mammary tumors [2]. Over the years, considerable indirect and limited direct evidence has emerged that suggests that an almost identical retrovirus to the MMTV, plus additional cofactors, may influence human breast carcinogenesis. This virus has become commonly known as HHMMTV. In addition, evidence has recently emerged that suggests additional viruses, such as the HPV and EBV, may also initiate or promote breast carcinogenesis [3,4,5,6,7].

HHMMTV and MMTV

In 1971, Moore et al [2] demonstrated that human milk from women who are at high risk for breast cancer contains particles that are morphologically similar to the MMTV. As shown in Fig. 1, these particles have a 'mushroom' shape, with spikes on the viral envelope. Schlom et al [8] showed that such particles had reverse transcriptase activity, which is found in oncogenic retroviruses. Evidence has since accumulated showing the presence of a retrovirus that is homologous to MMTV in human breast cancer tissues [9,10], in cultures of normal human breast cells [11] and in cultures of human breast cancer cells [12,13].

thumbnailFigure 1. Electron microscopy images of human and mouse mammary viruses taken in 1971. (a) Electron microscope image (×180,000) of particles from human milk. These particles are almost certainly the virions of the HHMMTV. (b) Image (×180,000) of particles from mouse milk. These particles are of the MMTV. The blurred edges of the particle images appear to be due to protein surface projections on the membrane of the viruses. The morphological characteristics of the particles in both the human and mouse milks appear to be almost identical and are unique among all viruses. When these characteristics are considered in conjunction with the 98% homology of the nucleotide sequences between the HHMMTV and MMTV, it appears likely that these viruses are variants of each other. Reprinted by permission from Nature [2] copyright 1971, Macmillan Magazines Ltd

In 1971, Charney and Moore [14] showed that the serum of humans with breast cancer decreased the virility of MMTV, which suggested that antibodies to proteins of the virus may be present in humans. Antibodies that are reactive with MMTV are present at much higher levels in serum of humans with breast cancer than in serum of healthy women [15]. Such antibody levels in women with breast cancer vary from below 5% (in Chinese) to over 60% (in East Africans) among different populations [15]. In addition, Stewart et al [16] collated data that suggest that the geographic variation in human breast cancer parallels the presence of the wild, but common house mouse, which may have acted as an animal host of the MMTV.

Gene sequences that are congruent with those of MMTV were detected and cloned in human breast cancer tissues by Callahan et al in 1982 [17]. Such detection had been difficult because of the presence of endogenous retroviral sequences within the human genome that are homologous with MMTV sequences. This problem has been largely resolved by Wang et al [18] by using sequences that are homologous to MMTV sequences, with low homology to human endogenous retroviruses. MMTV env gene sequences were found in 30-40% of breast cancer tissues in women from various populations. The INT6 gene is a common integration site for MMTV in mouse mammary tumours, and a human homologue with identical INT6 peptide has been identified in human breast cancer tissues [19].

Gene products of MMTV are present in concentrations that are 1000-10,000 times greater in malignant than in normal cells of mice [20]. It is not known whether this phenomenon occurs with respect to HHMMTV, but it may explain the difficulty experienced by Wang et al [18] in detecting the HHMMTV in normal breast epithelial cells. Endogenous HHMMTV has since been detected in normal breast epithelial cells by Soble et al [21] and our group (Rawlinson et al, unpublished data). The MMTV is highly mammotrophic, but it can cause lymphomas in mice [20]. The HHMMTV also appears to be mammotrophic [18]. However, HHMMTV has recently been identified in both breast and lymphoma tissues in several women with simultaneous diagnosis of breast cancer and non-Hodgkins lymphoma [22]. Non-Hodgkins lymphoma occurs more frequently in women with breast cancer than in the general population [23]. In vitro studies of human breast cancer cell lines [24] have shown that administration of oestrogen followed by progesterone stimulates the expression of human endogenous retroviruses in the genome.

The MMTV may be exogenous or endogenous [25]. The exogenous MMTV particles are transmitted in maternal milk but are not infectious for other mice [25]. The endogenous noninfectious MMTV particles are transmitted as part of the germline DNA [25]. Although both exogenous and endogenous forms of the virus appear able to induce mammary carcinogenesis independently in some mouse strains, they may also combine and be carcinogenic in the breast [25]. This phenomenon of recombination of exogenous and endogenous retroviruses, which then induce cell proliferation, is known in other viruses [26]. Therefore, it is possible that recombination of exogenous and endogenous HHMMTV may occur, potentially resulting in enhanced carcinogenesis.

Hormone and MMTV synergy

There is experimental evidence that glucocorticoids, insulin, epidermal growth factors, oestrogens and progestins synergize with MMTV in genetically susceptible female mice to cause mammary cancers [20]. Male mice are also exposed to exogenous and endogenous MMTV. Although endogenous MMTV has been isolated in the testes of male mice, these mice very rarely develop mammary cancers [25]. One possibility is that circulating oestrogen levels in male mice are not sufficiently high to promote MMTV activity. However, an antigen that is related to MMTV has been identified in approximately 90% of human male mammary carcinomas [27].

It is possible that MMTV is the initiator, and oestrogens and other hormones are the promoters of some mammary cancers in mouse models. However, the presence of MMTV is not obligatory for all mouse mammary cancers [20].

Are there other viruses that cause breast cancer in humans?

It has been shown [3] that HPV can immortalize normal human mammary epithelial cells. This leads to the possibility that HPV may be associated with breast as well as cervical carcinogenesis. In 1992, Lonardo et al [4] demonstrated the presence of HPV type 16 in 29% of breast tumors and metastatic lymph nodes using polymerase chain reaction techniques. Recently, HPV-16 has been identified in both breast and cervical cancer tissues in Norwegian women with concurrent breast and cervical cancer [5]. In addition, HPV-33 has been identified in breast tumors of 41% of Chinese and 11% of Japanese women with breast cancer [6].

Bonnet et al [7] identified EBV in breast cancer tissues in French women. This finding has provoked controversy, because it has been suggested that the EBV identified by Bonnet et al may have been present in infected lymphocytes in the breast [28]. EBV is ubiquitous in the population and is present in many tissues. It is the initiator of Burkitt's lymphoma, and it is highly associated with some cancers of epithelial origin such as nasopharangeal carcinoma. Although speculative, it is possible that EBV may enhance the action of HHMMTV, because it is known that some viruses remain dormant unless activity is promoted by other viruses [29,30].

Diets, oestrogens and breast cancer

Endogenous oestrogens are central to the aetiology of breast cancer [31]; in the absence of oestrogens, breast cancer does not occur. A recent prospective study of Japanese women [32] indicated that levels of serum oestrogens are positively correlated with risk of breast cancer, with a greater than threefold odds ratio in women with the highest as compared with the lowest serum oestradiol.

In humans there are strong associations between dietary pattern and level of circulating oestrogens, with energy-rich diets correlated with high circulating oestrogens [33]. However, evidence from huge prospective studies [34] has strongly suggested that there is no association between dietary fats and breast cancer in humans. On the other hand, the individuals studied were all from Europe and North America, where the consumption of fats and energy far exceed those of populations with low risk of breast cancer. Well-conducted case–control and ecological studies in populations with low risk of breast cancer, such as Chinese, Japanese and Indonesian populations, have shown that the risk of breast cancer is up to seven times higher in women who consume the highest levels of fats and energy in those populations [35,36,37]. These findings parallel the consistent correlations between per capita fat and energy consumption and breast cancer risk between countries [38]. In addition, there is emerging evidence from studies in humans [39] that different types of dietary fat may have different influences on breast carcinogenesis. N-6 polyunsaturated fats (as found in vegetable margarines) may increase risk, and n-3 polyunsaturated fats may reduce risk.

The associations between consumption of fats and energy and mammary carcinogenesis in experimental rodents is well established [40]. Experimental evidence in mice has shown that diets that are high in n-6 polyunsaturated fats (mainly sourced from corn) are associated with high oestrogen receptor expression in mammary epithelial cells and increased incidence of mammary tumours [41]. In addition, such diets have been shown [42] to accelerate the transcription of endogenous MMTV and to accelerate carcinogenesis.

Epidemiology

The epidemiology of breast cancer is well established. The most striking features of human breast cancer are the 100-fold greater incidence in females than in males, and up to 10-fold greater incidence of breast cancer in Western as compared with some Asian countries [31]. There is increased risk of breast cancer associated with early age of menarche, late age of menopause, late age of first full-term pregnancy, alcohol consumption and increased postmenopausal weight [31]. It is also possible that some forms of breast cancer originate during foetal life [31]. With the exception of genetic influences, these epidemiological features of breast cancer are probably all associated directly or indirectly with oestrogen physiology, which in turn may be associated with maternal diets during gestation and lifetime diets [31]. The viral/diet/hormone hypothesis is compatible with these epidemiological features, particularly as endogenous retroviruses may remain dormant for decades.

The case against a viral aetiology of breast cancer

There is seemingly strong evidence against a infectious cause of some types of breast cancer that is transmitted by mothers milk. Nearly 30 years ago, Fraumeni and Miller [43] summarized this evidence. Breast cancer rates are low in countries where breast-feeding is prolonged, and rates are increasing in countries where breast-feeding is declining; breast cancer occurs equally in maternal and paternal lines; and mother and daughter occurrences of breast cancer are not associated with breast-feeding. In addition, in a recent, large, case-control study of over 5685 US women with breast cancer [44], no evidence was found that having been breast-fed increased breast cancer risk in either premenopausal or postmenopausal women. An implication of this study is that human mothers' milk does not transmit an infectious agent. However, it was also observed in that study that women with breast cancer had a strong familial history of breast cancer, an observation that is compatible with an endogenous virus transmitted with germline cells, which may influence carcinogenesis in genetically susceptible individuals.

Conclusion

When considered as a whole and as shown on Fig. 2, this evidence suggests that HHMMTV, and possibly other transmissable viruses, in association with diet, steroid and other hormones and genetic susceptibility, has a role in human breast carcinogenesis. It is possible that HHMMTV is transmitted as particles (virions) in mother's milk and as part of the endogenous viral genome in the germline. Given the precedence of the association between MMTV and murine cancer, it is also possible that the exogenous HHMMTV (as virions in human maternal milk) may combine with endogenous HHMMTV, which then has a carcinogenic influence. Given the strong evidence against a human milk-borne infectious agent, it may be that viral human breast carcinogenesis only occurs if the endogenous virus is present in the genome of the breast epithelial cells, in addition to the exogenous virus that may be present in breast milk. Diets with high intakes of energy may lead to increased levels of oestrogen and other hormones that may enhance expression of HHMMTV.

thumbnailFigure 2. Viral, diet and hormone breast cancer aetiology hypothesis.

Many of these possibilities were suggested nearly 30 years ago [45]. At that time there was concern that, if there was a human breast cancer virus that had the milk-transmitted and inherited characteristics of the MMTV, then primary prevention would probably be useless in the face of immunological tolerance. However, if the above hypotheses are shown to be true, then there is a possibility of primary prevention by dietary intervention aimed at a reduction in serum oestrogens, vaccine immunization for viral infections and the use of hormone-modifying agents such as tamoxifen for women with HHMMTV [46].

All of these hypotheses are testable.

Acknowledgement

Thanks to Caroline Ford for access to unpublished data and Thomas S Lawson who prepared the cartoon.

Abbreviations

EBV = Epstein-Barr virus; HHMMTV = human homologue of the mouse mammary tumour virus; HPV = human papillomavirus; MMTV = mouse mammary tumour virus.

References

  1. Bittner JJ: Possible relationship of the oestrogenic hormones, genetic susceptibility and milk influence in the production of mammary cancer in mice.

    Cancer Res 1943, 2:710-721. OpenURL

  2. Moore DH, Charney J, Kramarsky B, Lasfragues EY, Sarkar NH, Brennan MJ, Burrows JH, Sirsat SM, Paymaster JC, Vaidya AB: Search for a human breast cancer virus.

    Nature 1971, 229:611-615. PubMed Abstract OpenURL

  3. Band V, Zajchowski D, Kulesa V, Sager R: Human papilloma virus DNAs immortalize human mammary epithelial cells and reduce their growth factor requirements.

    Proc Natl Acad Sci USA 1990, 87:463-467. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  4. Lonardo DA, Venuti A, Marcante ML: Human papillomavirus in breast cancer.

    Breast Cancer Res Treat 1992, 21:95-100. PubMed Abstract OpenURL

  5. Hennig EM, Suo Z, Thoresen S, Holm R, Kvinnsland S, Nesland JM: Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III).

    Breast Cancer Res Treat 1999, 53:121-135. PubMed Abstract | Publisher Full Text OpenURL

  6. Yu Y, Morimoto T, Sasa M, Okazaki K, Harada Y, Fujiwara T, Irie Y, Takahashi E-I, Tanigami A, Izumi K: HPV33 DNA in premalignant and malignant breast lesions in Chinese and Japanese populations.

    Anticancer Res 1999, 19:5057-5062. PubMed Abstract OpenURL

  7. Bonnet M, Guinebretiere J-M, Kremmer E, Grunewald V, Benhamou E, Contesso G, Joab I: Detection of Epstein-Barr virus in invasive breast cancer.

    J Natl Cancer Inst 1999, 91:1376-1381. PubMed Abstract | Publisher Full Text OpenURL

  8. Schlom J, Spiegelman S, Moore D: RNA dependent DNA polymerase activity in virus like particles isolated from human milk.

    Nature 1971, 231:97-100. PubMed Abstract OpenURL

  9. Axel R, Schlom J, Spiegelman S: Presence in human breast cancer of RNA homologous to mouse mammary tumour virus RNA.

    Nature 1972, 235:32-36. PubMed Abstract OpenURL

  10. Vaidya AB, Black MM, Dion AS, Moore DH: Homology between human breast tumour RNA and mouse mammary tumour virus genome.

    Nature 1974, 249:565-567. PubMed Abstract OpenURL

  11. Furmanski P, Longley C, Fouchey D, Rich R, Rich MA: Normal human mammary cells in culture: evidence for oncornavirus like particles.

    J Natl Cancer Inst 1974, 52:975-977. PubMed Abstract OpenURL

  12. McGrath CM: Replication of mammary tumor virus in tumor cell cultures: dependence on hormone induced cellular organisation.

    J Natl Cancer Inst 1971, 47:455-467. PubMed Abstract OpenURL

  13. Keydar I, Ohno T, Nayak R, Sweet R, Simoni F, Weiss F, Karby S, Mesa-Tejada R, Spiegelman S: Properties of retrovirus like particles produced by a human breast carcinoma cell line: immunological relationship with mouse mammary tumor virus proteins.

    Proc Natl Acad Sci USA 1984, 81:4188-4192. PubMed Abstract OpenURL

  14. Charney J, Moore DH: Neutralisation of murine mammary tumour virus by sera of women with breast cancer.

    Nature 1971, 229:627-628. PubMed Abstract OpenURL

  15. Day NK, Witkin SS, Sarkar NH, Kinne D, Jussawalla DJ, Levin A, Hsia CC, Geller N, Good RA: Antibodies reactive with murine mammary tumor virus in sera of patients with breast cancer: geographic and family studies.

    Proc Natl Acad Sci USA 1981, 78:2483-2487. PubMed Abstract OpenURL

  16. Stewart THM, Sage RD, Stewart AFR, Cameron DW: Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus.

    Br J Cancer 2000, 82:446-451. PubMed Abstract | Publisher Full Text OpenURL

  17. Callahan R, Drohan W, Tronick S, Schlom J: Detection and cloning of human DNA sequences related to the mouse mammary tumor virus genome.

    Proc Natl Acad Sci USA 1982, 79:5503-5507. PubMed Abstract OpenURL

  18. Wang Y, Go V, Holland JF, Melana SM, Pogo BG-T: Expression of mouse mammary tumor virus-like env gene sequences in human breast cancer.

    Clin Cancer Res 1998, 4:2565-2568. PubMed Abstract OpenURL

  19. Miyazaki S, Imatani A, Ballard L, Marchetti A, Buttitta F, Albertsen H, Nevanlinna HA, Gallahan D, Callahan R: The chromosome location of the human homologue of the mouse mammary tumor-associated gene INT6 and its status in human breast carcinomas.

    Genomics 1997, 46:155-158. PubMed Abstract | Publisher Full Text OpenURL

  20. McGrath CM, Jones RFR: Hormonal induction of mammary tumor viruses and its implications for carcinogenesis.

    Cancer Res 1978, 38:4112-4125. PubMed Abstract OpenURL

  21. Soble S, Haislip A, Hill S, Garry R: Human sequences related to mouse mammary tumor virus.

    In: Proceedings of the 11th International Microbiology Congress. Sydney: International Association of Microbiologists; 1999., [abstract VW 4407] OpenURL

  22. Etkind P, Du J, Khan A, Pillitteri J, Wiernik PH: Mouse mammary tumor virus-like ENV gene sequences in human breast tumors and a lymphoma of a breast cancer patient.

    Clin Cancer Res 2000, 6:1273-1278. PubMed Abstract | Publisher Full Text OpenURL

  23. Stierer M, Rosen HR, Heinz R, Hanak M: Synchrony of malignant lymphoma and breast cancer.

    JAMA 1990, 263:2922-2923. PubMed Abstract | Publisher Full Text OpenURL

  24. Ono M, Kawakami M, Ushikubo H: Stimulation of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D.

    J Virol 1987, 61:2059-2062. PubMed Abstract OpenURL

  25. Golovkina TV, Jaffe AB, Ross SR: Coexpression of exogenous and endogenous mouse mammary tumor virus RNA in vivo results in viral recombination and broadens the virus host range.

    J Virol 1994, 68:5019-5026. PubMed Abstract OpenURL

  26. DiFronzo NL, Holland CA: A direct demonstration of recombination between an injected virus and endogenous viral sequences, resulting in the generation of mink cell focus-inducing viruses in AKR mice.

    J Virol 1993, 67:3763-3770. PubMed Abstract OpenURL

  27. Lloyd RV, Rosen PP, Sarkar NH, Jimenez D, Kinne DW, Menendez-Botet C, Schwartz MK: Murine mammary tumor virus related antigen in human male mammary carcinoma.

    Cancer 1983, 51:654-661. PubMed Abstract OpenURL

  28. Brink AATP, Brule AJC, van den Diest P, van Meijer CJLM: Detection of Epstein-Barr virus in invasive breast cancers [letter].

    J Natl Cancer Inst 2000, 92:655. PubMed Abstract | Publisher Full Text OpenURL

  29. McKeating JA, Griffiths PD, Weiss RA: HIV susceptibility conferred to human fibroblasts by cytomegalovirus-induced Fc receptor.

    Nature 1990, 343:659-661. PubMed Abstract | Publisher Full Text OpenURL

  30. Biegalke BJ, Geballe AP: Sequence requirements for activation of the HIV1 LTR by human cytomegalovirus.

    Virology 1991, 183:381-385. PubMed Abstract OpenURL

  31. Adami H-O, Signorello LB, Trichopoulos D: Toward an understanding of breast cancer etiology.

    Cancer Biol Semin 1998, 8:255-262. Publisher Full Text OpenURL

  32. Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE: A prospective study of estradiol and breast cancer in Japanese women.

    Cancer Epidemiol Biomarkers Prev 2000, 9:575-579. PubMed Abstract | Publisher Full Text OpenURL

  33. Goldin BR, Aldercreutz H, Gorbach SL, Woods MN, Dwyer JT, Conlon T, Bohn E, Gershoff SN: The relationship between estrogen levels and diets of Caucasian American and Oriental immigrant women.

    Am J Clin Nutr 1986, 44:945-953. PubMed Abstract OpenURL

  34. Hunter DJ, Spiegelman D, Adami HO, Beeson L, van den Brandt PA, Folsom AR, Fraser GE, Goldbohm A, Graham S, Howe GR, Kushi LH, Marshall JR, McDermott A, Miller AB, Speizer FE, Wolk A, Yaun S-S, Willett W: Cohort studies of fat intake and the risk of breast cancer-a pooled analysis.

    N Engl J Med 1996, 334:356-361. PubMed Abstract | Publisher Full Text OpenURL

  35. Yuan JM, Wang QS, Ross RK, Henderson BE, Yu MC: Diet and breast cancer in Shanghai and Tianjin, China.

    Br J Cancer 1995, 71:1353-1358. PubMed Abstract OpenURL

  36. Hirayama T: Epidemiology of breast cancer with special reference to the role of diet.

    Prev Med 1978, 7:173-195. PubMed Abstract OpenURL

  37. Wakai K, Dillon DS, Ohno Y, Prihartono J, Budiningsih S, Ramli M, Darwis I, Tjindarbumi D, Tjahjadi G, Soestrisno E, Roostini ES, Sakamoto G, Herman S, Cornain S: Fat intake and breast cancer risk in an area where fat intake is low: a case control study in Indonesia.

    Int J Epidemiol 2000, 29:20-28. PubMed Abstract | Publisher Full Text OpenURL

  38. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J:

    Cancer Incidence in Five Continents, Vol 7. Scientific publication 143. Lyon, France: IARC;. 1997. OpenURL

  39. Wolk A, Bergstrom R, Hunter D, Willett W, Ljung H, Holmberg L, Bergkvist L, Bruce A, Adami H-O: A prospective study of association of monounsaturated fat and other types of fat with risk of breast cancer.

    Arch Intern Med 1998, 158:41-45. PubMed Abstract | Publisher Full Text OpenURL

  40. Welsch CW: Enhancement of mammary tumorigenesis by dietary fat: review of potential mechanisms.

    Am J Clin Nutr 1987, 45:192-202. PubMed Abstract OpenURL

  41. Hilakivi-Clarke L, Stoica A, Raygada M, Martin MB: Consumption of a high fat diet alters estrogen receptor content, protein kinase C activity and mammary gland morphology in virgin and pregnant mice and female offspring.

    Cancer Res 1998, 58:654-660. PubMed Abstract OpenURL

  42. Etkind PR: Dietary effects on gene expression in mammary tumorigenesis.

    Adv Exp Med Biol 1995, 375:75-83. PubMed Abstract OpenURL

  43. Fraumeni JF, Miller RW: Breast cancer from breast feeding.

    Lancet 1971, ii:1196-1197. OpenURL

  44. Titus-Erstoff L, Egan KM, Newcomb PA, Baron JA, Stampfer M, Greenberg ER, Cole BF, Ding J, Willett W, Trichopoulos D: Exposure to breast milk in infancy and adult breast cancer risk.

    J Natl Cancer Inst 1998, 90:921-924. PubMed Abstract | Publisher Full Text OpenURL

  45. Anonymous: Human breast cancer virus? [editorial].

    Nature 1971, 229:593-594. PubMed Abstract OpenURL

  46. Jordan VC, Lababidi MK, Langan-Fahey S: Suppression of mouse mammary tumorigenesis by long term Tamoxifen therapy.

    J Natl Cancer Inst 1991, 83:492-496. PubMed Abstract | Publisher Full Text OpenURL