Breast Cancer and the Role of Cytokines in Regulating Estrogen Synthesis: An Emerging Hypothesis

I. Introduction II. Peripheral Estrogen Synthesis and Blood and Tissue Estrogens in Breast Cancer A. Peripheral estrogen synthesis B. Aromatase C. Estrone sulfatase D. E2DH E. Origins of breast tumor estrogens III. Influence of Breast Tumor Location on Enzyme Activities in Adjacent Tissues IV. Proposed Model for the Regulation of Estrogen Synthesis in Breast Tumors V. Evidence in Support of Proposed Model of Cytokine Regulation of Estrogen Synthesis A. Identification of factors that stimulate estrogen synthesis B. Potentiation of cytokine stimulation of estrogen synthesis VI. The Role of Soluble Cytokine Receptors in Cytokine Action A. Mechanism of cytokine action B. Regulation of gp80 and gp130 C. Regulation of IL-6 sR shedding VII. Origin of Estrogen-Stimulating Factors in Breast Tumors A. The role of cells of the immune system B. Macrophages and lymphocytes in breast tumors VIII. Regulation of Lymphocyte Cytokine Production A. Th1 and Th2-helper cells B. Dehydroepiandrosterone (DHA) and glucocorticoids IX. Clinical Observations Explained by Proposed Model of Cytokine Regulation of Estrogen Synthesis A. Septic shock B. The effect of aging on peripheral estrogen synthesis C. The effect of weight on peripheral aromatase activity D. The discriminant function test E. Stress and breast cancer F. Immunosuppression and breast cancer risk G. Failure of glucocorticoids to stimulate aromatase activity in vivo X. Summary and Future Perspectives ESTROGENS have a central role in the development and growth of hormone-dependent breast tumors (1, 2), although the highest incidence of breast cancer occurs in postmenopausal women at a time when ovarian production of estrogen has ceased. However, the enzymes required for the peripheral synthesis of estrogens are present in other body tissues, such as adipose (3, 4), but also in most samples of normal and malignant breast tissues (5). While there was originally some controversy (6) as to whether the activities of these enzymes within breast tumors could result in the production of sufficient estrogen to exert a biological effect, i.e., stimulate tumor growth, a number of factors have now been identified that can markedly enhance estrogen synthesis in breast cancer cells and fibroblasts derived from normal or malignant breast tissues. Recent advances in understanding the regulation of estrogen synthesis in the subclass of breast tumors that possesses the enzymes necessary for estrogen synthesis are considered in this review. Cytokines have emerged as being important regulators of estrogen synthesis in breast tissues, and a model is proposed for the involvement of the immune system and cytokines in controlling the peripheral synthesis of estrogens. For some time it has been known that peripheral estrogen formation is enhanced in obese or elderly subjects and that stress or immunosuppression may alter the risk of developing breast cancer. From the proposed model for the regulation of estrogen synthesis by cytokines, it is possible to suggest mechanisms to account for the effects of obesity and aging on estrogen synthesis and for the altered risks of breast cancer associated with stress or immunosuppression. A major objective of this review is to stimulate further research to support such a role for cytokines in the control of estrogen synthesis in breast cancer. Peripheral estrogen synthesis results from the activities of three main enzymes. The aromatase enzyme complex, which converts adrenal androstenedione to estrone, is widely the body in adipose and tissues (3, Aromatase activity is also in normal breast and of breast tumors of the from androstenedione is to by and this estrogen can as a for the formation of the action of sulfatase Estrone is to the by The and E2DH enzymes have been and has regulation at the the of the of formation from it that the of this was to body weight (3, normal weight subjects of androstenedione is to in obese subjects this can to The in the peripheral of androstenedione to associated with obesity most for the risk that such subjects have for the development of subjects in peripheral estrogen synthesis also occurs with aging The in aromatase activity that occurs with as from in vivo was in in which adipose aromatase activity was in in in in aromatase activity was in adipose from women as with tissues from women that from women a in which was of aromatase in adipose from and of women to with important to from the the regulation of aromatase activity in was the by and that the in the of could markedly stimulate aromatase was that the could also stimulate in aromatase activity While glucocorticoids can stimulate aromatase activity in to for such a role for glucocorticoids in vivo The peripheral of androstenedione to in women or with results being in in The for the of glucocorticoids to enhance in vivo aromatase activity but in the review in the of of the control of aromatase Blood and breast of are for the estrogens the of in is for Estrone may as a for the formation of by sulfatase The activity of sulfatase is the aromatase in normal and malignant breast tissues in with the is present in most breast tumors (5). formation of the sulfatase was to account for a of breast tumor that the aromatase a model to hormone-dependent to of the was to in from the of from androstenedione or is to by was originally that as was for the of and and that it could in or However, of or in women with breast tumors that within tumors was to For and malignant breast a was E2DH activity in adipose the breast and the of obesity of the is now that E2DH is present in breast tumors and that this is for the of to to the of estrogens in the of postmenopausal of breast tumor estrogen a that breast tumors may have now estrogen with in normal and malignant breast tissues. A has emerged from these that the of and in normal and malignant breast tissues are the in estrogen and in are in malignant in normal breast A from these was that the to was that for to from of breast estrogens was the that in postmenopausal women the in estrogen production that occurs at tumor of with being in tumors from and postmenopausal women estrogens in breast tumors could from the the of estrogen or tumors While some was for in in tumors was and as and was the major of tumor and is that the enzymes necessary for synthesis are present in most breast in formation a major to the of these to on the of estrogen in breast a was to of estrogen from the to from in synthesis in normal and malignant breast tissues some breast tumors there was of in but in to of the of tumors was identified as from in in formation in normal breast was in to tumors estrogen from in vivo and in that in breast was to and that the activities of the and sulfatase enzymes in malignant normal breast tissues with the of breast tumor to the that breast tumors may or factors that could the of estrogen within tumors but also stimulate the activities of the enzymes in estrogen synthesis Support for this was by results from a that a the of but breast tumors and E2DH activity in adipose to the tumor E2DH activity within breast tumors was also to with activity in normal breast some from the tumor that the of a tumor within the breast could also aromatase activity in the breast in which the tumor was and the important that aromatase activity in the breast was in has now been in further of and activity and other results results from three have that the of a tumor within the breast is to aromatase and activity in tissues. that sulfatase activity may also by tumor has also been but further are required to the of this The that the of a tumor within the breast could and sulfatase activities in tissues to the and of the From this research it has been possible to a model to account for the regulation of estrogen synthesis in breast tumors in which cells of the immune system have important role as a major of the factors that stimulate tumor estrogen The proposed which is in with the in in the review. Proposed model for the regulation of estrogen synthesis in breast Breast cancer cells are in a of cells and with to of the of a tumor being of and and cells androstenedione is to by the aromatase enzyme of from by sulfatase is also important of tumor with being to by E2DH I. and tumors in to such as and by tumor The cytokines IL-6 and which are by cells of the immune system and also by cells and have a central role in tumor estrogen The of IL-6 to stimulate estrogen synthesis can by as a result of the of the gp130 that is in the The can also in a and can the of IL-6 to stimulate aromatase of IL-6 sR is by with the being by the The gp130 is and it is possible that IL-6 in with the IL-6 sR can IL-6 in cells the cytokines in estrogen synthesis which may account for the of most breast Breast tumor cells in a of other cells that cells and However, it is now that a to of breast tumors can of cells of the immune system that the and lymphocytes that are by such as and by tumor A is for tumor growth, and there is now that may important of factors that stimulate development in breast tumors of breast tumors aromatase activity most tumors have sulfatase and E2DH enzyme (5). to the of aromatase in breast tumors have for a and for this enzyme of aromatase activity in fibroblasts or breast cancer cells have that a of aromatase activity is present in cells of the of E2DH has that the enzyme is in the of malignant cells and in IL-6 and tumor have emerged as in estrogen synthesis in breast cancer IL-6 and stimulate and sulfatase activities and can also to enhance the activities of these enzymes. While IL-6 can by breast fibroblasts and a major of IL-6 within breast tumors is to the The of IL-6 to stimulate aromatase activity can markedly by the IL-6 IL-6 sR is by malignant cells and fibroblasts derived from but but a major of IL-6 sR within breast tumors is from the and of IL-6 sR from malignant cells can by with the being to the in The IL-6 IL-6 sR can with the gp130 of the and this is required for the of that results from IL-6 to the gp130 to it is possible that in with could stimulate aromatase activity in other cells within the body the is also but to that IL-6 in with the IL-6 may also enhance E2DH activity in breast cancer although there is for such which is by and cells of the immune can of the gp130 of the and this for the that occurs IL-6 and in to stimulate estrogen it has emerged that there is a system of estrogen synthesis within breast tumors that to by The result of the stimulation of estrogen synthesis may account for the of in breast to support the that breast tumors factors that estrogen the breast tumor and E2DH activity in adipose this of to was by breast tumor effect on the of was was that from breast but normal breast could also stimulate E2DH formation of from activity in breast cancer cells and aromatase activity in breast fibroblasts in the of Breast which is from breast that are in women and which may associated with risk of breast cancer was also to to stimulate aromatase and E2DH activities in breast cells of breast tumor and to the of factors that could stimulate estrogen the growth and was also identified in breast tumor of to stimulate E2DH and aromatase activities but also to the of growth such as or cytokines, such as to stimulate the activities of these enzymes The of to with was as it been that activity was associated with of the proposed model of the regulation of estrogen synthesis by cytokines, it is of that some of have been to production of IL-6 and by is possible that a of in breast tumors may have a Potentiation of growth and cytokine stimulation of activity by in breast cancer from A. with from The cytokines and IL-6 in by and cytokines to stimulate aromatase activity in breast fibroblasts in the of However, the of IL-6 in was that of that IL-6 was the major aromatase present in IL-6 was also identified in from breast fibroblasts as of the factors for the of this to stimulate E2DH activity in breast cancer cells IL-6 also E2DH activity in these cells although to enzyme activity was in The to which E2DH activity was that by a of that other factors may also present in the and to the effect of IL-6 on E2DH is by and with adipose a of in the of postmenopausal a of and IL-6 was for to stimulate E2DH markedly the of IL-6 to stimulate E2DH activity although in this of cytokines also sulfatase activity in cells and aromatase activity in fibroblasts derived from normal and malignant breast tissues, with and IL-6 also to enhance the activities of these enzymes cytokines that are of the IL-6 and can also aromatase activity in adipose cells of aromatase activity by cytokines in fibroblasts derived from normal breast from a effect on aromatase activity as a aromatase when in the of but of markedly aromatase activity with IL-6 and with from A. 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The of on and cells has now been the role that cytokines have in estrogen synthesis in peripheral tissues, the is being it in some that factors in estrogen synthesis may result from the to or in support of this was in by and that estrogen markedly in shock and in shock subjects with normal subjects is now known that IL-6 and are in with and the by important in support of a role for these cytokines in peripheral estrogen synthesis and in with shock or IL-6 and are in subjects with and this most for the estrogen in these from with from The the that IL-6 has a central role in peripheral aromatase it possible to suggest a to account for the that has been as a result of from in vivo and in it is now that the in the production of the adrenal and that occurs with aging results in in production of the cytokines, which production of IL-6 by and effect on aromatase a for the that occurs for peripheral which and sulfatase can as with IL-6 to the activities of these enzymes. to being by cells of the immune is also by However, a of is by from obese subjects by of although the of adipose in which of obese subjects is to to production of it is to by production of from and the discriminant function test as a for women breast cancer The of of of women at risk of developing breast cancer and also associated with in women with breast cancer. to that the discriminant function i.e., the of and which are derived from adrenal to that of derived from the of such While it was the test such it was that the discriminant function test in a of cytokine production is in women with breast and in the the production of cytokines production of IL-6 result in in estrogen synthesis in peripheral and breast tissues. is also some that in to malignant cells also cytokines The role of stress in the risk of breast cancer is but a for a number of in women with breast cancer but breast the in which stress the development of breast cancer is as to breast cancer occurs most in postmenopausal a time when production is in in stress the in the of cytokine production and could result in estrogen to stress A tumor have in tumor and tumor growth with The incidence of breast cancer in is in a normal such as to production and the of cytokines by these in women of cytokines to stimulate estrogen synthesis in breast and other peripheral tissues and may to the incidence of breast cancer in these Support for the of to a in cytokine production and estrogen synthesis has been of from of a in cytokine and to stimulate aromatase activity with from a with breast cancer. IL-6 is important in vivo aromatase this some for the as in the of glucocorticoids to stimulate in but in vivo aromatase activity can aromatase activity in in the of but the for this and the factors the of to stimulate aromatase activity are A with a in the of has been in as being for aromatase but is known it is possible that it in to the number of on cells the of which may present in in some to stimulate aromatase However, glucocorticoids to in vivo to IL-6 as of a to the to stress and of IL-6 by glucocorticoids in vivo could account for to stimulate in vivo aromatase The results from the research have to a understanding of the of the regulation of estrogen synthesis in breast tumors and a possible for the effects of aging and body weight on peripheral estrogen synthesis and stress on the risk of breast cancer. is that cytokines, such as IL-6 and have important in estrogen synthesis in breast cancer cells although it is that other factors to of the immune which are to tumors by are the major of cytokines and that have been to stimulate estrogen However, IL-6 derived from and from within the breast are also to to the production of A major that has emerged from of the research the to factors that stimulate estrogen synthesis is the that most factors that stimulate enzyme activity in also growth The possible to these was for which E2DH also to growth A possible for this may with the that and which most of the cytokines that stimulate estrogen are to to the growth of tumor i.e., However, in vivo with the of the i.e., estrone, and the stimulation of the activities of the enzymes that these sufficient to the normal effect that cytokines have on it is possible that the production of IL-6 sR by tumor fibroblasts and lymphocytes the normal that to these cells of in to which can result in or of growth factors and it is possible that IL-6 sR production by cells that are in to malignant cells is normal growth mechanisms are tumor cells to The that production of estrogens tumor cells to the effects of the immune system is in with the some by and that the immune was to have for the of tumor growth and the effects of the immune system on tumor growth the of some of the that are to the also a that in to IL-6 and which in growth, other cytokines may stimulate estrogen synthesis but also for which aromatase activity is known to stimulate the of breast cancer cells and to by but breast cancer cells is also possible that which has been to by derived from breast but and which can E2DH activity may also have a role in the regulation of breast tumor estrogen The has been for research the regulation of breast tumor estrogen have the enzymes in estrogen synthesis been and but for some of the enzymes have also been However, it is that the of enzyme may sufficient to the of estrogen synthesis some in the it necessary to for the growth of hormone-dependent breast to the cytokines control enzyme activity may to the development of of the that to estrogen synthesis in the of cytokines with and the factors that production and could to the development of cytokine that could have a role in the of breast cancer. as in this or a such as or have important role in the it possible to further of in cytokine production and a role for this in the of breast cancer. the of or for the of breast cancer to further