In vivo modulation of natural killer cell activity by tamoxifen in patients with bilateral primary breast cancer

Robinson, Eliezer; Rubin, Dina; Mekori, T.; Segal, Ricardo; Pollack, Shirley

doi:10.1007/bf01525437

Cited by 40 publications

(19 citation statements)

References 18 publications

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“…To gain more insights into antiestrogeninduced resistance, we have addressed whether antiestrogeninduced TGFβ could contribute to resistance development due to its well-known functions as an immune regulator. When peripheral blood lymphocytes of breast cancer patients were analyzed, antiestrogens apparently displayed only weak direct effects both with respect to function and quantity of circulating lymphocytes (23,24). However, the consequences of antiestrogen treatment on the interaction of tumor cells with its immediate surrounding tissue, composed of stromal fibroblasts, endothelial cells, and a variety of infiltrating immune cells, are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Antiestrogens Induce Transforming Growth Factor β–Mediated Immunosuppression in Breast Cancer

et al. 2010

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Antiestrogens are universally used to treat estrogen receptor-positive breast cancer, but relapses occur commonly due to the development of drug resistance. The ability of antiestrogen to induce transforming growth factor β (TGFβ) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGFβ on cancer progression but also at the level of its effects on the host immune system. To evaluate the potential role of tumor-derived, antiestrogen-induced TGFβ as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor infiltrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneic MLTR, antiestrogentreated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8 + T cells, and suppressed the generation of cytotoxic effector cells in a TGFβ-dependent manner.Furthermore, we documented induction of regulatory T cells in CD4 + T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells. These effects were reversed by addition of a TGFβ neutralizing antibody. Our findings offer evidence that antiestrogen induces immunosuppression in the tumor microenvironment, through a TGFβ-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer. Cancer Res; 70(4); 1314-22.

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Section: Discussionmentioning

confidence: 99%

Antiestrogens Induce Transforming Growth Factor β–Mediated Immunosuppression in Breast Cancer

et al. 2010

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“…Rotstein et al and subsequently Robinson et al reexamined the effects of tamoxifen on immunity in breast cancer patients and demonstrated modulatory effects [19,20]. Rotstein et al studied the function of peripheral lymphocytes derived from breast cancer patients (n=23) treated with tamoxifen for 1.5 to 2 years [19].…”

Section: Tamoxifen As An Immune Modulatormentioning

confidence: 99%

The Effects of Tamoxifen on Immunity

Behjati¹,

Frank²

2009

CMC

104

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Tamoxifen is a widely known anti-estrogen which has been employed in adjuvant treatment of earlystage, estrogen-sensitive breast cancer for over 20 years. Less well known are the effects of tamoxifen on immune function, which we discuss here. We review the growing body of evidence which demonstrates immunomodulatory effects of tamoxifen, including in vitro and in vivo studies as well as observations made in breast cancer patients treated with tamoxifen. Taken together these studies suggest that tamoxifen is capable of inducing a shift from cellular (T-helper 1) to humoral (T-helper 2) immunity. Interestingly, the immunomodulatory effects of tamoxifen appear to be independent of the estrogen-receptor and may be mediated through the multi-drug resistance gene product, Permeability-glycoprotein, for which a role in immunity has recently emerged. We furthermore discuss the clinical implications of the immunomodulatory effects of tamoxifen which are twofold. First, tamoxifen may be utilized in the treatment of immune-mediated disorders, particularly of those arising from aberrant T-helper 1 cell activity, including allograft rejection, Crohn's disease, and Th1-mediated autoimmune conditions such as diabetes mellitus, scleroderma, and multiple sclerosis. Second, given that cellular T-helper 1 immunity is targeted against cancer cells, the tamoxifeninduced shift away from cellular immunity represents a significant step in fostering a cancerogenic environment. This may limit the anti-cancer effects of tamoxifen and thus explain why tamoxifen is inferior compared to other anti-estrogens in preventing disease recurrence in early-stage breast tumors.

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“…NCA against NK-sensitive K562 cells was tested, as previously described, 23,24 at E:T ratios of 50:1, 25:1 and 12:1. NCA is also presented as the number of LUs in 10 7 effector cells (1 LU is the number of effector cells that lyse 20% of target cells).…”

Section: Nca Assaymentioning

confidence: 99%

Increased emotional distress in daughters of breast cancer patients is associated with decreased natural cytotoxic activity, elevated levels of stress hormones and decreased secretion of Th1 cytokines

Cohen

Klein²,

Kuten³

et al. 2002

Intl Journal of Cancer

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DBCP who are aware of their increased risk of developing breast cancer may suffer from high emotional distress. Chronic stress may interfere with NCA and low NCA is associated with increased cancer risk. We studied 80 DBCP and 47 age-and education-matched healthy females (controls). Heparinized venous blood (30 ml) was drawn from all subjects between 8 and 9 A.M., and each participant answered a set of psychologic questionnaires. In addition, the firstmorning urine sample was collected. DBCP scored significantly higher in emotional distress compared to controls. Levels of stress hormones in DBCP were higher and in vitro secretion of IL-2, IL-12 and IFN-␥ lower compared to controls. NCA against NK-resistant (MCF-7, COLO-205, U937) and NK-sensitive (K562) cell lines was significantly lower in DBCP and much less augmented by in vitro preincubation with IL-2 or IL-12 compared to controls. NCA and in vitro Th1 cytokine secretion were inversely correlated with the degree of emotional distress and the level of stress hormones in blood or urine. High emotional distress and elevated levels of stress hormones are associated with impaired immune surveillance functions in DBCP. This may contribute to the increased risk of DBCP to develop breast cancer. An interventional trial to enhance coping and reduce stress levels may help to decrease the risk for breast cancer onset in DBCP. © 2002 Wiley-Liss, Inc. Key words: chronic stress; daughters of breast cancer patients; natural cytotoxic activity; Th1 cytokines; stress hormonesThe critical question in immunosurveillance against cancer, which has so far remained unanswered, is whether differences between individuals with regard to immunologic host-defense mechanisms can predict the future development of cancer. Various in vivo studies in humans and mice have shown the significant role of different natural cytotoxic lymphocyte populations in preventing the development of cancer or its metastases. 1-4 However, only a few studies have investigated NCA of peripheral blood lymphocytes among healthy individuals in a general population or those at increased risk of developing cancer. 5-7 NCA has also been demonstrated to be an independent prognostic marker in patients with cancer. 8,9 Imai et al. 10 showed that selected lifestyle factors, such as maintaining body weight, not smoking, increasing intake of green vegetables and moderate alcohol consumption, may have an effect on natural cytotoxicity and that NCA can be increased by altering several lifestyle factors. Other studies have shown that restricted lifestyle changes, such as increasing exercise, losing weight and reducing fat and alcohol intake, are associated with a significant reduction in breast cancer risk (reviewed by Chlebowski 11 ).Whether emotional distress is associated with the onset of cancer in general and of breast cancer in particular has long been debated. Some studies have suggested that the overall prevalence of breast cancer is increased in women who have experienced stressful life events. 12,13 In contrast, the...

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In vivo modulation of natural killer cell activity by tamoxifen in patients with bilateral primary breast cancer

Cited by 40 publications

References 18 publications

Antiestrogens Induce Transforming Growth Factor β–Mediated Immunosuppression in Breast Cancer

Antiestrogens Induce Transforming Growth Factor β–Mediated Immunosuppression in Breast Cancer

The Effects of Tamoxifen on Immunity

Increased emotional distress in daughters of breast cancer patients is associated with decreased natural cytotoxic activity, elevated levels of stress hormones and decreased secretion of Th1 cytokines

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