- Email: [email protected]
Estrogen receptor (ER) in breast cancer tissue of premenopausal patients: are some ER− findings false due to down-regulation?
Correspondence
1069
Estrogen receptor (ER) in breast cancer tissue of premenopausal patients: are some ER findings false due to down-regulation? Estrogen receptor (ER) and progesterone receptor (PR) status at the time of breast carcinoma surgery is used as a marker of both prognosis and hormone dependency to guide adjuvant therapy [1]. This approach is based on the accumulated knowledge that the presence of estrogen and/or progesterone receptors typically suggests slower-growing tumors, amenable to hormonal manipulation [2]. In most clinical studies and therapy recommendations, breast cancer is considered hormone dependent if at least one receptor type is present in the tumor tissue. ER content is often highly variable in different cells of the same tumor [3,4]. In some patients, breast cancer tissue is only ER+ or only PR+. Among 3359 cases in the Danish Breast Cancer Cooperative Group [5], the incidence of ER+/PR+ subtype was 62.9% of all cases, ER/PR subtype 17.6%, ER+/ PR subtype 13.9%, while ER/PR+ subtype was 5.6%. The ER/PR tumors are always considered hormone independent and these patients are treated with cytostatic drugs without hormone manipulations, although it is known that <10% of them show some response to hormonal treatment. Since estrogen regulates the expression of progesterone receptors [6], it can be assumed that ER/PR+ tumors have low undetectable levels of functional ERs, while ER+/PR tumors might have dysfunctional ERs. It was already suggested that ER/PR+ breast carcinomas are biologically different from ER positive/PR positive tumors and have a poor clinical outcome [7]. The expression of ER and PR in normal breast tissue is highly variable, with many apparently negative cells [8], for instance, in premenopausal normal breast tissue, 6% of cells are ER positive and 29% PR positive [9]. It was reported that, expression of ER declines in the normal breast tissue as the menstrual cycle progresses [10], and that tamoxifen therapy increases the mean percentage ER positivity in normal ductal tissue [8]. These reports suggest that ER content in the normal premenopausal breast tissue can be down-regulated by the estrogen exposure. The obvious question is whether some of our ER/PR premenopausal patients might really belong to the ER+/PR subtype, but due to the estrogen exposure, the ER content in tumor tissue is reduced below detection.
Possible evidence for the proposed false ER negativity in premenopausal breast cancer patients might be hidden in results of the Danish Breast Cancer Cooperative Group [5]. They have reported that the incidence of the ER/PR subtype increased with age prior to about age 50 but remained unchanged subsequently. ER+/PR+ subtype increased with age continually, with a sudden decrease in the rate of increase around age 44. The incidence of ER+/PR subtype increased rapidly during the menopausal period but only slightly afterwards, while the ER/PR+ subtype increased until about age 43 and decreased subsequently. In short, their data suggest that in the perimenopausal age group (age 43–50), the incidences of ER/PR is increased. Tarone and Chu [11] have also reported that the age-specific rates of ER breast cancer cease increasing after 50 years of age, but age-specific rates of ER+ breast cancer continue to increase after 50 years of age. Data reported by Li Cl et al. [12] also showed that among patients younger than 50, larger share of ER/PR tumors can be found. For 1998, they have reported that the ER/PR share was 39.8% (age 20–39) and 25.4% (age 40–49) of all cases. In older age groups, the share of receptor negative tumors ranged from 21.9% to 14.3%. It is known for the normal breast tissue that higher levels of ER gene mRNA are found in breasts of women during the luteal phase of the menstrual cycle [13], suggesting that the level of ER gene mRNA is not down-regulated by the estrogen exposure. To test the presented hypothesis, negative immunohistochemical ER finding in premenopausal patients should be compared with levels of mRNA expression of the ER gene in tumor tissue. In this way, some patients might be recognised as ER+ and hormonal treatment can be reconsidered as an option.
References [1] Pujol P, Daures JP, Thezenas S, Guilleux F, Rouanet P, Grenier J. Changing estrogen and progesterone receptor patterns in breast carcinoma during the menstrual cycle and menopause. Cancer 1998;83:698–705.
1070 [2] Major MA. Clinical trials update: medical management of advanced breast cancer. Cancer Nurs 2003; 26(Suppl. 6):10S–5S. [3] Kommoss F, Pfisterer J, Idris T, Giese E, Sauerbrei W, Schafer W et al. Steroid receptors in carcinoma of the breast. Results of immunocytochemical and biochemical determination and their effects on short-term prognosis. Anal Quant Cytol Histol 1994;16:203–10. [4] van Agthoven T, Timmermans M, Foekens JA, Dorssers LC, Henzen-Logmans SC. Differential expression of estrogen, progesterone, and epidermal growth factor receptors in normal, benign, and malignant human breast tissues using dual staining immunohistochemistry. Am J Pathol 1994;144:1238–46. [5] Yasui Y, Potter JD. The shape of age-incidence curves of female breast cancer by hormone-receptor status. Cancer Causes Control 1999;10(Oct):431–7. [6] Mies C, Voigt W. Sequence analysis of the DNA binding domain of the estrogen receptor gene in ER (+)/PR () breast cancer. Diagn Mol Pathol 1996;5:39–44. [7] Keshgegian AA, Cnaan A. Estrogen receptor-negative, progesterone receptor-positive breast carcinoma: poor clinical outcome. Arch Pathol Lab Med 1996;120: 970–3. [8] Walker KJ, Price-Thomas JM, Candlish W, Nicholson RI. Influence of the antioestrogen tamoxifen on normal breast tissue. Br J Cancer 1991;64:764–8.
Correspondence [9] Jacquemier JD, Hassoun J, Torrente M, Martin PM. Distribution of estrogen and progesterone receptors in healthy tissue adjacent to breast lesions at various stages – immunohistochemical study of 107 cases. Breast Cancer Res Treat 1990;15:109–17. [10] Khan SA, Rogers MA, Khurana KK, Meguid MM, Numann PJ. Estrogen receptor expression in benign breast epithelium and breast cancer risk. J Natl Cancer Inst 1998;90:37–42. [11] Tarone RE, Chu KC. The greater impact of menopause on ER than ER+ breast cancer incidence: a possible explanation (United States). Cancer Causes Control 2002;13(Feb):7–14. [12] Li CI, Daling JR, Malone KE. Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 2003;21:28–34. [13] Boyd M, Hildebrandt RH, Bartow SA. Expression of the estrogen receptor gene in developing and adult human breast. Breast Cancer Res Treat 1996;37:243–51.
Sven Kurbel Damir Kovac ˇic ´ Jozo Kristek Vladimir ˇSisˇljagic ´ Ivan Mihaljevic ´ Osijek University Hospital Osijek, Croatia
doi:10.1016/j.mehy.2004.12.003
Could repetitive transcranial magnetic stimulation be effective in autism? I have read with great interest the recent article, ‘‘Could ECT be effective in autism?’’ by Dhossche and Stanfill [1]. The authors suggested that ECT may be effective in some autism because certain types of autism may be the earliest expression of catatonia and ECT is effective in treating catatonia [1]. Furthermore, the findings that GABAergic mechanisms may play a role in the pathogenesis of autism [2] and ECT can enhance GABA function [3] further support their hypothesis that ECT can be effectively treat autism [1]. However, in their article, Dhossche and Stanfill stated that there may be the greatest deterrent to use ECT in autism from ECT sentiment as well as from medical community. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive approach to briefly stimulate or inhibit cortical brain areas, has been used or explored in the treatment of various psychiatric disorders in recent years [4]. Here, I suggest that rTMS could be a potential strategy for the treatment of autism. First, rTMS has
been reported to be effective for the treatment of catatonia [5,6]. The intricate link between autism and catatonia suggests that rTMS could be effective for certain types of autism. Second, an early disturbance in the serotonin system affecting brain development is a potential mechanism to autism [7]. In animal study, chronic rTMS has been shown to induce subsensitivity of presynaptic serotonergic autoreceptor activity in rat brain [8]. Therefore, an early rTMS treatment in autistic children may help to normalize serotonergic dysfunction, and may reverse or even prevent symptoms from developing completely. Finally, a large part of children with autistic disorder function in the mentally retarded range of intellectual function. Recent studies had shown that female schizophrenic patients had improvement in cognitive tests after rTMS treatment [9]. Autistic disorder is a developmental behavioural disorder. The symptoms of autism develop at an early age and do not seem to improve overtime.
1069
Estrogen receptor (ER) in breast cancer tissue of premenopausal patients: are some ER findings false due to down-regulation? Estrogen receptor (ER) and progesterone receptor (PR) status at the time of breast carcinoma surgery is used as a marker of both prognosis and hormone dependency to guide adjuvant therapy [1]. This approach is based on the accumulated knowledge that the presence of estrogen and/or progesterone receptors typically suggests slower-growing tumors, amenable to hormonal manipulation [2]. In most clinical studies and therapy recommendations, breast cancer is considered hormone dependent if at least one receptor type is present in the tumor tissue. ER content is often highly variable in different cells of the same tumor [3,4]. In some patients, breast cancer tissue is only ER+ or only PR+. Among 3359 cases in the Danish Breast Cancer Cooperative Group [5], the incidence of ER+/PR+ subtype was 62.9% of all cases, ER/PR subtype 17.6%, ER+/ PR subtype 13.9%, while ER/PR+ subtype was 5.6%. The ER/PR tumors are always considered hormone independent and these patients are treated with cytostatic drugs without hormone manipulations, although it is known that <10% of them show some response to hormonal treatment. Since estrogen regulates the expression of progesterone receptors [6], it can be assumed that ER/PR+ tumors have low undetectable levels of functional ERs, while ER+/PR tumors might have dysfunctional ERs. It was already suggested that ER/PR+ breast carcinomas are biologically different from ER positive/PR positive tumors and have a poor clinical outcome [7]. The expression of ER and PR in normal breast tissue is highly variable, with many apparently negative cells [8], for instance, in premenopausal normal breast tissue, 6% of cells are ER positive and 29% PR positive [9]. It was reported that, expression of ER declines in the normal breast tissue as the menstrual cycle progresses [10], and that tamoxifen therapy increases the mean percentage ER positivity in normal ductal tissue [8]. These reports suggest that ER content in the normal premenopausal breast tissue can be down-regulated by the estrogen exposure. The obvious question is whether some of our ER/PR premenopausal patients might really belong to the ER+/PR subtype, but due to the estrogen exposure, the ER content in tumor tissue is reduced below detection.
Possible evidence for the proposed false ER negativity in premenopausal breast cancer patients might be hidden in results of the Danish Breast Cancer Cooperative Group [5]. They have reported that the incidence of the ER/PR subtype increased with age prior to about age 50 but remained unchanged subsequently. ER+/PR+ subtype increased with age continually, with a sudden decrease in the rate of increase around age 44. The incidence of ER+/PR subtype increased rapidly during the menopausal period but only slightly afterwards, while the ER/PR+ subtype increased until about age 43 and decreased subsequently. In short, their data suggest that in the perimenopausal age group (age 43–50), the incidences of ER/PR is increased. Tarone and Chu [11] have also reported that the age-specific rates of ER breast cancer cease increasing after 50 years of age, but age-specific rates of ER+ breast cancer continue to increase after 50 years of age. Data reported by Li Cl et al. [12] also showed that among patients younger than 50, larger share of ER/PR tumors can be found. For 1998, they have reported that the ER/PR share was 39.8% (age 20–39) and 25.4% (age 40–49) of all cases. In older age groups, the share of receptor negative tumors ranged from 21.9% to 14.3%. It is known for the normal breast tissue that higher levels of ER gene mRNA are found in breasts of women during the luteal phase of the menstrual cycle [13], suggesting that the level of ER gene mRNA is not down-regulated by the estrogen exposure. To test the presented hypothesis, negative immunohistochemical ER finding in premenopausal patients should be compared with levels of mRNA expression of the ER gene in tumor tissue. In this way, some patients might be recognised as ER+ and hormonal treatment can be reconsidered as an option.
References [1] Pujol P, Daures JP, Thezenas S, Guilleux F, Rouanet P, Grenier J. Changing estrogen and progesterone receptor patterns in breast carcinoma during the menstrual cycle and menopause. Cancer 1998;83:698–705.
1070 [2] Major MA. Clinical trials update: medical management of advanced breast cancer. Cancer Nurs 2003; 26(Suppl. 6):10S–5S. [3] Kommoss F, Pfisterer J, Idris T, Giese E, Sauerbrei W, Schafer W et al. Steroid receptors in carcinoma of the breast. Results of immunocytochemical and biochemical determination and their effects on short-term prognosis. Anal Quant Cytol Histol 1994;16:203–10. [4] van Agthoven T, Timmermans M, Foekens JA, Dorssers LC, Henzen-Logmans SC. Differential expression of estrogen, progesterone, and epidermal growth factor receptors in normal, benign, and malignant human breast tissues using dual staining immunohistochemistry. Am J Pathol 1994;144:1238–46. [5] Yasui Y, Potter JD. The shape of age-incidence curves of female breast cancer by hormone-receptor status. Cancer Causes Control 1999;10(Oct):431–7. [6] Mies C, Voigt W. Sequence analysis of the DNA binding domain of the estrogen receptor gene in ER (+)/PR () breast cancer. Diagn Mol Pathol 1996;5:39–44. [7] Keshgegian AA, Cnaan A. Estrogen receptor-negative, progesterone receptor-positive breast carcinoma: poor clinical outcome. Arch Pathol Lab Med 1996;120: 970–3. [8] Walker KJ, Price-Thomas JM, Candlish W, Nicholson RI. Influence of the antioestrogen tamoxifen on normal breast tissue. Br J Cancer 1991;64:764–8.
Correspondence [9] Jacquemier JD, Hassoun J, Torrente M, Martin PM. Distribution of estrogen and progesterone receptors in healthy tissue adjacent to breast lesions at various stages – immunohistochemical study of 107 cases. Breast Cancer Res Treat 1990;15:109–17. [10] Khan SA, Rogers MA, Khurana KK, Meguid MM, Numann PJ. Estrogen receptor expression in benign breast epithelium and breast cancer risk. J Natl Cancer Inst 1998;90:37–42. [11] Tarone RE, Chu KC. The greater impact of menopause on ER than ER+ breast cancer incidence: a possible explanation (United States). Cancer Causes Control 2002;13(Feb):7–14. [12] Li CI, Daling JR, Malone KE. Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 2003;21:28–34. [13] Boyd M, Hildebrandt RH, Bartow SA. Expression of the estrogen receptor gene in developing and adult human breast. Breast Cancer Res Treat 1996;37:243–51.
Sven Kurbel Damir Kovac ˇic ´ Jozo Kristek Vladimir ˇSisˇljagic ´ Ivan Mihaljevic ´ Osijek University Hospital Osijek, Croatia
doi:10.1016/j.mehy.2004.12.003
Could repetitive transcranial magnetic stimulation be effective in autism? I have read with great interest the recent article, ‘‘Could ECT be effective in autism?’’ by Dhossche and Stanfill [1]. The authors suggested that ECT may be effective in some autism because certain types of autism may be the earliest expression of catatonia and ECT is effective in treating catatonia [1]. Furthermore, the findings that GABAergic mechanisms may play a role in the pathogenesis of autism [2] and ECT can enhance GABA function [3] further support their hypothesis that ECT can be effectively treat autism [1]. However, in their article, Dhossche and Stanfill stated that there may be the greatest deterrent to use ECT in autism from ECT sentiment as well as from medical community. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive approach to briefly stimulate or inhibit cortical brain areas, has been used or explored in the treatment of various psychiatric disorders in recent years [4]. Here, I suggest that rTMS could be a potential strategy for the treatment of autism. First, rTMS has
been reported to be effective for the treatment of catatonia [5,6]. The intricate link between autism and catatonia suggests that rTMS could be effective for certain types of autism. Second, an early disturbance in the serotonin system affecting brain development is a potential mechanism to autism [7]. In animal study, chronic rTMS has been shown to induce subsensitivity of presynaptic serotonergic autoreceptor activity in rat brain [8]. Therefore, an early rTMS treatment in autistic children may help to normalize serotonergic dysfunction, and may reverse or even prevent symptoms from developing completely. Finally, a large part of children with autistic disorder function in the mentally retarded range of intellectual function. Recent studies had shown that female schizophrenic patients had improvement in cognitive tests after rTMS treatment [9]. Autistic disorder is a developmental behavioural disorder. The symptoms of autism develop at an early age and do not seem to improve overtime.