Clinical Oncology(1992) 4:4-5 I~) 1992The Royal College of Radiologists
Clinical Oncology
Editorial G r o w t h H o r m o n e and Breast Cancer B. A. Stoll Oncology Department, St Thomas' Hospital, London SE1 7EH, UK
There is increasing evidence of the role of growth hormone (GH) in the development and progression of human mammary cancer. Several studies have reported occasional tumour regression following treatment with somatostatin analogues in women with metastatic breast cancer [1-4]. In our present state of knowledge, the mechanism of tumour growth inhibition may be either direct or indirect. A direct effect is possible through somatostatin receptors which have been reported in some human breast cancers [5]. The likelihood of response to treatment by somatostatin, and also the prognosis, are both claimed to be related to the presence of somatostatin receptors [6]. An alternative explanation for tumour growth inhibition by somatostatin is through suppression of GH secretion which may be stimulating tumour growth. Insulin-like growth factor 1 (IGF1) whose' level is regulated by GH, is known to exert a potent mitogenic effect on the growth of human mammary cancer cell lines [7]. Receptors for IGF1 have been shown in 90% of primary breast cancer cell lines and there is a positive relationship between the level of IGF1 receptors and that of oestrogen and progesterone receptors [6]. In addition, a significant reduction in IGF1 levels has been noted in breast cancer patients treated by tamoxifen and this has led to the suggestion that antioestrogens may act in part by reducing G H output, and thus the stimulation of tumour growth by IGF1 [8]. Recent evidence suggests that GH and IGF1 may also have a role in the promotion of carcinogenesis in human mammary tissue. Experimental evidence suggests that factors which increase proliferative activity also increase Susceptibility of mammary tissue to malignant change [9], and in the human its proliferative activity is greatest at puberty [10]. That growth hormone can stimulate such proliferative activity is shown by the observation of accelerated development of mammary tissue in prepubertal girls with isolated GH deficiency, following their treatment by recombinant growth hormone [11]. Measurements close to the time of tumour promotion are most likely to provide insight into the factors promoting the development of breast cancer. The hypothesis relating breast cancer risk to early maturity in girls can be tested clinically by measuring circulating IGF1 levels together with oestrogen and androgen profiles in girls around the time of puberty,
and relating them to stages in breast development and linear growth. The ductal epithelium of normal breast tissue contains abundant IGF1 receptors [12], and circulating IGF levels peak at puberty. It is therefore possible that IGF interacts with sex steroids derived from the adrenal cortex [13] in causing the earliest development of breast growth in the female. In vitro studies suggest that other growth factors such as platelet-derived growth factor and fibroblast growth factor may also be necessary for stimulation of proliferative activity by IGF1 [14]. It is conventionally assumed that the liberation of oestradiol from ovarian follicles triggers the onset of the adolescent growth spurt but in Western girls, the growth spurt begins an average of 3.5 years before the menarche [15]. The onset of breast development similarly appears an average of 2.5 years before the menarche, so that both breast growth and linear growth are already decelerating when oestradiol levels peak just before the menarche. Early menarche increases breast cancer risk [16] but the conventional wisdom that oestrogen plays the leading role in human mammary carcinogenesis is now being questioned. Biological observations on human mammary tissue suggest that the role Of oestrogen is mainly to sensitize breast epithelium to the effect of growth factors [17]. IGF1 has a major role in promoting normal cell growth and division, and in vitro observations suggest that its oncogenic potential requires overexpression of IGF1 receptors [18]. It has been hypothesized that the role of oestrogen in the promotion of breast cancer may be to sensitize mammary cells to the proliferative effect of IGF1 by increasing the expression of IGF1 receptor [19]. Further evidence suggesting a role for growth hormone in human mammary carcinogenesis comes from recent prospective studies showing an association between increased risk of cancer and tall stature. Three of the studies involved more than 500000 women [20]. In Sweden, Tornberg and coworkers [21] showed the risk to be increased by 10% for every 5 cm of additional height, the effect being greater in premenopausal women. In Norway, Tretli and colleagues [22] showed a 40% increased risk for 15 cm additional height and this applied both to preand postmenopausal women. In the USA, London and associates [23] showed that an 8 cm increase in
Growth Hormone and Breast Cancer
height increased risk in premenopausal women by 10% and in postmenopausal women by 30%. The trend to increasing tallness in adults is associated with an earlier adolescent growth spurt [24]. A precocious growth spurt will be reflected in an early high circulating level of growth hormone and IGF1. On the basis that both relative tallness and relatively early menarche increase the risk of breast cancer, it has been postulated that earlier exposure of developing breast tissue to a combination of IGF and sex steroids will increase and prolong pubertal proliferative activity and may promote carcinogenesis in a susceptible mammary epithelium [25].
5
9.
10. 11. 12.
13. 14.
References
15. 16.
1. Vermin PH, Peyrat JP, Bonneterre J, et al. Effect of the long lasting somatostatin analog SMS 201-995 (Sandostatin) in advanced breast cancer. Anticancer Res 1989; 9:153-6. 2. Pollak MN, Polychronakos C, Guyda H. Somatostatin analogue SMS 201-995 reduces serum IGF1 levels in patients with neoplasms potentially dependent on IGF1. Anticancer Res 1989; 9:889-92. 3. Manni A, Boucher AE, Demers LM, et al. Endocrine effects of combined somatostatin analog and bromocriptine therapy in women with advanced breast cancer. Breast Cancer Res Treat 1989; 14:289-98. 4. Stolfi R, Parisi AM, Natoli C, et al. Advanced breast cancer; response to somatostatin. Anticancer Res 1990; 10:203-4. 5. Reubi JC, Waser B, Foekens JA, et al. Somatostatin receptor incidence and distribution in breast cancer using receptor autoradiography; relationship to IGF receptors. Int J Cancer 1990; 46:416-20. 6. Klijn JGM. Second international symposium on hormonal manipulation of cancer; peptides, growth factors and new antisteroidal agents. Ann Oncol 1991; 2:183-9. 7. Huff KK, Knabbe C, Lindsey R, et al. Multihormonal regulation of insulin-like growth factor 1-related protein in MCF-7 human breast cancer cells. Mol Endocrinol 1988; 2:200-8. 8. Pollak M, Costantino J, Polychronakos C, et al. Effect of
17.
18. 19. 20. 21.
22. 23. 24. 25.
tamoxifen on serum insulin-like growth factor levels in Stage 1 breast cancer patients. J Natl Cancer Inst 1990; 82:1693-7. Russo JH, Calaf G, Russo J. Hormones and proliferative activity in breast tissue. In: Stoll BA, editor. Approaches to breast cancer prevention. Dordrecht: Kluwer, 1991:35-51. Drife JO. Avoiding hormone-related risk factors. In: Stoll BA, editor. Approaches to breast cancer prevention. Dordrecht: Kluwer, 1991:61-72. Darendeliler F, Hindmarsh PC, Preece MA. Growth hormone increases rate of pubertal maturation. Acta Endocrinol 1990; 122:414-6. Pekonen F, Partanen S, M~ikinen T, et al. Receptors for epidermal growth factor and insulin growth factor 1 and their relation to steroid receptors in human breast cancer. Cancer Res 1988; 48:1343-7. Stirling HF, Kelnar JH. Adrenarche. Growth Matt 1989; 1:68. Stiles CD, Antoniades HN, Capone GT, et al. Dual control of cell growth by somatomedin and platelet-derived growth factor. Proc Natl Acad Sci USA 1979; 76:1279-83. Ratcliffe S. The clinical consequences of an extra sex chromosome. Growth Matt 1991; 6:2-4. Ewertz M. Risk factors for breast cancer and their prognostic significance. Acta Oncol 1988; 27:733-7. Anderson TJ, Battersby S. The involvement of oestrogen in the development and function of the normal breast; histological evidence. Proc R Soc Edin 1980; 95B:23-32. Kaleko M, Rutter WJ, Miller AD. Overexpression of the human IGF1 receptor promotes ligand dependent neoplastic transformation. Mol Cell Biol 1990; 10:464-73. Stewart AJ, Johnson MD, May FEB, et al. Role of IGFs and IFG1 receptor in the estrogen stimulated proliferation of human breast cancer cells. J Biol Chem 1990; 265:21172-8. Byers TE, Williarnson DR. Diet, alcohol, body size a n d prevention of breast cancer. In: Stoll BA, editor. Approaches to breast cancer prevention. Dordrecht: Kluwer, 1991:113-34. Tornberg SA, Holm LE, Carstensen JM. Breast cancer risk in relation to serum cholesterol, serum beta lipoprotein, height, weight and blood pressure. Acta Oncol 1988; 27:31-7. Tretli S. Height and weight in relation to breast cancer morbidity and mortality; a prospective survey of 570000 women in Norway. Int J Cancer 1989; 44:23-30. London SJ, Colditz GA, Stampfer MJ. Prospective study of relative weight, height and risk of breast cancer. J A M A 1989; 262:2853-8. Preece MA. The trend to greater height and earlier maturation. Growth Matt 1989; 1:3-4. Stoll BA. Safety of growth hormone. Lancet 1991; 337:108.
Clinical Oncology
Editorial G r o w t h H o r m o n e and Breast Cancer B. A. Stoll Oncology Department, St Thomas' Hospital, London SE1 7EH, UK
There is increasing evidence of the role of growth hormone (GH) in the development and progression of human mammary cancer. Several studies have reported occasional tumour regression following treatment with somatostatin analogues in women with metastatic breast cancer [1-4]. In our present state of knowledge, the mechanism of tumour growth inhibition may be either direct or indirect. A direct effect is possible through somatostatin receptors which have been reported in some human breast cancers [5]. The likelihood of response to treatment by somatostatin, and also the prognosis, are both claimed to be related to the presence of somatostatin receptors [6]. An alternative explanation for tumour growth inhibition by somatostatin is through suppression of GH secretion which may be stimulating tumour growth. Insulin-like growth factor 1 (IGF1) whose' level is regulated by GH, is known to exert a potent mitogenic effect on the growth of human mammary cancer cell lines [7]. Receptors for IGF1 have been shown in 90% of primary breast cancer cell lines and there is a positive relationship between the level of IGF1 receptors and that of oestrogen and progesterone receptors [6]. In addition, a significant reduction in IGF1 levels has been noted in breast cancer patients treated by tamoxifen and this has led to the suggestion that antioestrogens may act in part by reducing G H output, and thus the stimulation of tumour growth by IGF1 [8]. Recent evidence suggests that GH and IGF1 may also have a role in the promotion of carcinogenesis in human mammary tissue. Experimental evidence suggests that factors which increase proliferative activity also increase Susceptibility of mammary tissue to malignant change [9], and in the human its proliferative activity is greatest at puberty [10]. That growth hormone can stimulate such proliferative activity is shown by the observation of accelerated development of mammary tissue in prepubertal girls with isolated GH deficiency, following their treatment by recombinant growth hormone [11]. Measurements close to the time of tumour promotion are most likely to provide insight into the factors promoting the development of breast cancer. The hypothesis relating breast cancer risk to early maturity in girls can be tested clinically by measuring circulating IGF1 levels together with oestrogen and androgen profiles in girls around the time of puberty,
and relating them to stages in breast development and linear growth. The ductal epithelium of normal breast tissue contains abundant IGF1 receptors [12], and circulating IGF levels peak at puberty. It is therefore possible that IGF interacts with sex steroids derived from the adrenal cortex [13] in causing the earliest development of breast growth in the female. In vitro studies suggest that other growth factors such as platelet-derived growth factor and fibroblast growth factor may also be necessary for stimulation of proliferative activity by IGF1 [14]. It is conventionally assumed that the liberation of oestradiol from ovarian follicles triggers the onset of the adolescent growth spurt but in Western girls, the growth spurt begins an average of 3.5 years before the menarche [15]. The onset of breast development similarly appears an average of 2.5 years before the menarche, so that both breast growth and linear growth are already decelerating when oestradiol levels peak just before the menarche. Early menarche increases breast cancer risk [16] but the conventional wisdom that oestrogen plays the leading role in human mammary carcinogenesis is now being questioned. Biological observations on human mammary tissue suggest that the role Of oestrogen is mainly to sensitize breast epithelium to the effect of growth factors [17]. IGF1 has a major role in promoting normal cell growth and division, and in vitro observations suggest that its oncogenic potential requires overexpression of IGF1 receptors [18]. It has been hypothesized that the role of oestrogen in the promotion of breast cancer may be to sensitize mammary cells to the proliferative effect of IGF1 by increasing the expression of IGF1 receptor [19]. Further evidence suggesting a role for growth hormone in human mammary carcinogenesis comes from recent prospective studies showing an association between increased risk of cancer and tall stature. Three of the studies involved more than 500000 women [20]. In Sweden, Tornberg and coworkers [21] showed the risk to be increased by 10% for every 5 cm of additional height, the effect being greater in premenopausal women. In Norway, Tretli and colleagues [22] showed a 40% increased risk for 15 cm additional height and this applied both to preand postmenopausal women. In the USA, London and associates [23] showed that an 8 cm increase in
Growth Hormone and Breast Cancer
height increased risk in premenopausal women by 10% and in postmenopausal women by 30%. The trend to increasing tallness in adults is associated with an earlier adolescent growth spurt [24]. A precocious growth spurt will be reflected in an early high circulating level of growth hormone and IGF1. On the basis that both relative tallness and relatively early menarche increase the risk of breast cancer, it has been postulated that earlier exposure of developing breast tissue to a combination of IGF and sex steroids will increase and prolong pubertal proliferative activity and may promote carcinogenesis in a susceptible mammary epithelium [25].
5
9.
10. 11. 12.
13. 14.
References
15. 16.
1. Vermin PH, Peyrat JP, Bonneterre J, et al. Effect of the long lasting somatostatin analog SMS 201-995 (Sandostatin) in advanced breast cancer. Anticancer Res 1989; 9:153-6. 2. Pollak MN, Polychronakos C, Guyda H. Somatostatin analogue SMS 201-995 reduces serum IGF1 levels in patients with neoplasms potentially dependent on IGF1. Anticancer Res 1989; 9:889-92. 3. Manni A, Boucher AE, Demers LM, et al. Endocrine effects of combined somatostatin analog and bromocriptine therapy in women with advanced breast cancer. Breast Cancer Res Treat 1989; 14:289-98. 4. Stolfi R, Parisi AM, Natoli C, et al. Advanced breast cancer; response to somatostatin. Anticancer Res 1990; 10:203-4. 5. Reubi JC, Waser B, Foekens JA, et al. Somatostatin receptor incidence and distribution in breast cancer using receptor autoradiography; relationship to IGF receptors. Int J Cancer 1990; 46:416-20. 6. Klijn JGM. Second international symposium on hormonal manipulation of cancer; peptides, growth factors and new antisteroidal agents. Ann Oncol 1991; 2:183-9. 7. Huff KK, Knabbe C, Lindsey R, et al. Multihormonal regulation of insulin-like growth factor 1-related protein in MCF-7 human breast cancer cells. Mol Endocrinol 1988; 2:200-8. 8. Pollak M, Costantino J, Polychronakos C, et al. Effect of
17.
18. 19. 20. 21.
22. 23. 24. 25.
tamoxifen on serum insulin-like growth factor levels in Stage 1 breast cancer patients. J Natl Cancer Inst 1990; 82:1693-7. Russo JH, Calaf G, Russo J. Hormones and proliferative activity in breast tissue. In: Stoll BA, editor. Approaches to breast cancer prevention. Dordrecht: Kluwer, 1991:35-51. Drife JO. Avoiding hormone-related risk factors. In: Stoll BA, editor. Approaches to breast cancer prevention. Dordrecht: Kluwer, 1991:61-72. Darendeliler F, Hindmarsh PC, Preece MA. Growth hormone increases rate of pubertal maturation. Acta Endocrinol 1990; 122:414-6. Pekonen F, Partanen S, M~ikinen T, et al. Receptors for epidermal growth factor and insulin growth factor 1 and their relation to steroid receptors in human breast cancer. Cancer Res 1988; 48:1343-7. Stirling HF, Kelnar JH. Adrenarche. Growth Matt 1989; 1:68. Stiles CD, Antoniades HN, Capone GT, et al. Dual control of cell growth by somatomedin and platelet-derived growth factor. Proc Natl Acad Sci USA 1979; 76:1279-83. Ratcliffe S. The clinical consequences of an extra sex chromosome. Growth Matt 1991; 6:2-4. Ewertz M. Risk factors for breast cancer and their prognostic significance. Acta Oncol 1988; 27:733-7. Anderson TJ, Battersby S. The involvement of oestrogen in the development and function of the normal breast; histological evidence. Proc R Soc Edin 1980; 95B:23-32. Kaleko M, Rutter WJ, Miller AD. Overexpression of the human IGF1 receptor promotes ligand dependent neoplastic transformation. Mol Cell Biol 1990; 10:464-73. Stewart AJ, Johnson MD, May FEB, et al. Role of IGFs and IFG1 receptor in the estrogen stimulated proliferation of human breast cancer cells. J Biol Chem 1990; 265:21172-8. Byers TE, Williarnson DR. Diet, alcohol, body size a n d prevention of breast cancer. In: Stoll BA, editor. Approaches to breast cancer prevention. Dordrecht: Kluwer, 1991:113-34. Tornberg SA, Holm LE, Carstensen JM. Breast cancer risk in relation to serum cholesterol, serum beta lipoprotein, height, weight and blood pressure. Acta Oncol 1988; 27:31-7. Tretli S. Height and weight in relation to breast cancer morbidity and mortality; a prospective survey of 570000 women in Norway. Int J Cancer 1989; 44:23-30. London SJ, Colditz GA, Stampfer MJ. Prospective study of relative weight, height and risk of breast cancer. J A M A 1989; 262:2853-8. Preece MA. The trend to greater height and earlier maturation. Growth Matt 1989; 1:3-4. Stoll BA. Safety of growth hormone. Lancet 1991; 337:108.
