There is substantial evidence from in-vivo studies that an earlyJonathan J.Li1,2 step in estrogen... more There is substantial evidence from in-vivo studies that an earlyJonathan J.Li1,2 step in estrogen carcinogenesis in the hamster kidney is
Both natural and synthetic estrogens are capable of inducing renal neoplasms in Syrian hamsters w... more Both natural and synthetic estrogens are capable of inducing renal neoplasms in Syrian hamsters with an incidence approaching 100%/. Neither the sequence of events nor the mechanisms involved in estrogen carcinogenesis in this model have been established. Results presented here indicate that estrogen induces renal tubular damage in the hamster kidney that is progressive and cumulative. Tubular injury was evident both as abnormal or lost microvilli, accumulation of cytoplasmic lipid droplets, vacuolization, and increases in secondary and tertiary lysosomes after 1.5 months of diethylstilbestrol (DES) treatment. Increasing tubular damage was evidenced by the detachment of tubular cells, cell debris, and occluded renal tubular lumens. In an effort to repair proximal tubular damage in the hamster kidney elicited by estrogens, a 4.0-fold increase in proximal tubule BrdU labeling was evident at 4 months of DES or 170-estradiol (E2) treatment and in earlier estrogen treatment periods (1-3 ...
... 3854-3856, October 1980] 0008-54 72 780/004 0-OOOOS02.00 Letter to the Editor Correspondence ... more ... 3854-3856, October 1980] 0008-54 72 780/004 0-OOOOS02.00 Letter to the Editor Correspondence re: Young C. Lin, Deanna J. Talley, and Claude A. Villee. ... 2614-2617. 1979. 18 Mawhmney, M G., and Neubauer, BL Actions of estrogen in the male Invest. Urol , 76 409-...
Advances in Experimental Medicine and Biology, Feb 1, 2008
... 19 Estrogen-Induced Breast Oncogenesis: Modulation by an Aurora Kinase Inhibitor Sara Antonia... more ... 19 Estrogen-Induced Breast Oncogenesis: Modulation by an Aurora Kinase Inhibitor Sara Antonia Li, Luke KT Lam, Nayaz Ahmed, Adrianne E. Hontz, and Jonathan J. Li Introduction ... Williams and Wikins, Baltimore. 28. Harrington EA, Bebbington D, Moore J, et al. ...
Abstract The estrogen-induced progesterone receptor in the untransformed hamster kidney has been ... more Abstract The estrogen-induced progesterone receptor in the untransformed hamster kidney has been further characterized. The ability of various estrogenic hormones to induce specific renal progesterone receptor in the hamster was 17β-estradiol= estrone> estriol> 17α- ...
Our previous studies demonstrated a specific progesterone receptor in the estrogen-induced and -d... more Our previous studies demonstrated a specific progesterone receptor in the estrogen-induced and -dependent hamster renal carcinoma and provided evidence that estrogen treatment induces a 4S progesterone-binding component in renal cytosol of the hamster. This latter finding ...
ESTROGENS have been implicated as causative agents in tumor development for more than half a cent... more ESTROGENS have been implicated as causative agents in tumor development for more than half a century. A number of mammalian species, including primates as well as man, are susceptible to the formation of neoplasms, both benign and malignant, at various organ sites after ...
The activity of microsomal estrogen 2-/4-hydroxylase enzyme (ESH), which mediates the formation o... more The activity of microsomal estrogen 2-/4-hydroxylase enzyme (ESH), which mediates the formation of catechol estrogens, was determined in the hamster kidney and liver under different endocrine states and after treatment with diethylstilbestrol (DES) and 5 alpha-dihydrotestosterone alone or in combination. Our results indicate that at least 64% of the renal ESH activity is localized in the kidney cortex. Employing either estrone or 17 beta-estradiol as substrate, a significant decline in renal ESH activity was observed after castration, with estrone remaining the more active substrate. In contrast, hepatic ESH activity, which is about 2.0- to 2.5-fold higher than the kidney enzyme, was not altered after gonadectomy using either estrogen substrate. A further reduction in renal ESH activity was found in DES-treated castrated hamsters when estrone was used. Androgen treatment resulted in a nearly 2-fold increase in kidney ESH activity using either estrogen substrate. Animals treated concomitantly with DES and 5 alpha-dihydrotestosterone exhibited catechol estrogen formation similar to untreated castrate hamster kidney microsomes. In contrast, hamster liver ESH activity was unaffected by androgen treatment. HPLC profiles of the catechol estrogen monomethyl ethers confirm these changes. Hamster kidney ESH activity in females was only 5-7% of that in intact males. Ovariectomy resulted in a 3-fold increase in the activity of this microsomal enzyme with either estrogen substrate. ESH activity was substantially increased in uteri of intact animals after androgen treatment. These data clearly demonstrate that ESH activity is under androgen control, particularly in the hamster kidney of both sexes, and may be pertinent in understanding the antagonism of this hormone in estrogen-induced renal tumorigenesis.
Comparison of the soluble estradiol receptor proteins in the hypothalamus and uterus of the golde... more Comparison of the soluble estradiol receptor proteins in the hypothalamus and uterus of the golden Syrian hamster revealed that both have sedimentation coefficients of 8S in a low ionic strength buffer and migrate similarly on analytical disc-gel electrophoresis in both 5% and 7% acrylamide gels. The competition of [3H]-17beta-estradiol binding by unlabeled estrogenic as well as nonestrogenic compounds was similar with the receptors present in the two tissues. The affinity constants for the hypothalamic and uterine receptors were 4.3 X 10-9M-1 and 1.6 X 10-10M-1, respectively; the number of binding sites when expressed on an equivalent protein basis (i.e. 1 mg/ml) was 0.18 X 10-10M and 3.1 X 10-10M, respectively. Identical amounts of soluble receptors with similar sedimentation characteristics were found in hypothalami from male and female animals gonadectomized 64 h prior to use. A titration of binding sites in the uteri of intact and ovariectomized animals revealed decreased binding in the supernatant preparation from intact animals, probably due to the presence of bound endogenous unlabeled hormone.
A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclin... more A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclins D1 and D3 was examined during estradiol-17beta (E(2))-induced mammary tumorigenesis in female August Copenhagen Irish (ACI) rats. Low serum E(2) levels ( approximately 60-120 pg/ml) were sufficient to induce mammary gland tumors (MGTs) that remarkably resemble human ductal breast cancer (BC) at the histopathologic and molecular levels. Western blot analysis of the E(2)-induced MGTs revealed a marked rise in cyclins D1 (24-fold), D3 (9-fold) and cdk4 (3-fold) expression compared with age-matched untreated controls. Small focal dysplasias with large, pale staining nuclei were commonly seen at 3-3.6 months, large focal dysplasias, including atypical ductal hyperplasia at 3.6-4.3 months, ductal carcinoma in-situ (DCISs) at 4.3-5.0 months, and 100% incidence of invasive ductal BC/frank tumors at 5-6 months were detected after E(2) treatment. Immunohistochemical analysis of serial sections of focal dysplasias, DCISs and invasive ductal carcinomas showed overexpression of cyclins D1, D3, estrogen receptor-alpha (ERalpha) and progesterone receptor (PR). However, cyclin D3 expression, unlike D1, was confined essentially to early pre-malignant lesions (focal dysplasias and DCISs) and primary MGTs with <1-5% of resting and normal hyperplastic breast cells staining positive. The kinase activity for cyclins D1 and D3, using retinoblastoma (Rb) as a substrate, in E(2)-induced MGTs and their binding to cdk4 was significantly elevated. Semi-quantitative reverse transcriptase PCR analysis of the E(2)-induced MGTs exhibited increased expression of cyclins D1 (2.9-fold) and D3 (1.4-fold) mRNA, indicating that their elevated protein expression was due in part to an increase in mRNA transcription. However, when analyzed by quantitative real-time Q-PCR, these genes were not amplified. These data indicate that in female ACI rat mammary glands, E(2)-induced pre-malignant lesions differentially and selectively express cyclins D1 and D3, thus contributing to a distinct growth advantage of these pre-neoplasias relative to E(2)-elicited normal hyperplasia.
An estrogen receptor-driven, multistep process for estrogen carcino- genesis in the Syrian hamste... more An estrogen receptor-driven, multistep process for estrogen carcino- genesis in the Syrian hamster kidney is proposed. Because in this species the reproductive and urogenital tracts arise from the same embryonic germinal ridge, it is evident that the kidney has carried over genes that are responsive to estrogens. Using in situ hybridization, overexpression of early estrogen-response genes, i.e., c-myc and c-fos,
There is substantial evidence from in-vivo studies that an earlyJonathan J.Li1,2 step in estrogen... more There is substantial evidence from in-vivo studies that an earlyJonathan J.Li1,2 step in estrogen carcinogenesis in the hamster kidney is
Both natural and synthetic estrogens are capable of inducing renal neoplasms in Syrian hamsters w... more Both natural and synthetic estrogens are capable of inducing renal neoplasms in Syrian hamsters with an incidence approaching 100%/. Neither the sequence of events nor the mechanisms involved in estrogen carcinogenesis in this model have been established. Results presented here indicate that estrogen induces renal tubular damage in the hamster kidney that is progressive and cumulative. Tubular injury was evident both as abnormal or lost microvilli, accumulation of cytoplasmic lipid droplets, vacuolization, and increases in secondary and tertiary lysosomes after 1.5 months of diethylstilbestrol (DES) treatment. Increasing tubular damage was evidenced by the detachment of tubular cells, cell debris, and occluded renal tubular lumens. In an effort to repair proximal tubular damage in the hamster kidney elicited by estrogens, a 4.0-fold increase in proximal tubule BrdU labeling was evident at 4 months of DES or 170-estradiol (E2) treatment and in earlier estrogen treatment periods (1-3 ...
... 3854-3856, October 1980] 0008-54 72 780/004 0-OOOOS02.00 Letter to the Editor Correspondence ... more ... 3854-3856, October 1980] 0008-54 72 780/004 0-OOOOS02.00 Letter to the Editor Correspondence re: Young C. Lin, Deanna J. Talley, and Claude A. Villee. ... 2614-2617. 1979. 18 Mawhmney, M G., and Neubauer, BL Actions of estrogen in the male Invest. Urol , 76 409-...
Advances in Experimental Medicine and Biology, Feb 1, 2008
... 19 Estrogen-Induced Breast Oncogenesis: Modulation by an Aurora Kinase Inhibitor Sara Antonia... more ... 19 Estrogen-Induced Breast Oncogenesis: Modulation by an Aurora Kinase Inhibitor Sara Antonia Li, Luke KT Lam, Nayaz Ahmed, Adrianne E. Hontz, and Jonathan J. Li Introduction ... Williams and Wikins, Baltimore. 28. Harrington EA, Bebbington D, Moore J, et al. ...
Abstract The estrogen-induced progesterone receptor in the untransformed hamster kidney has been ... more Abstract The estrogen-induced progesterone receptor in the untransformed hamster kidney has been further characterized. The ability of various estrogenic hormones to induce specific renal progesterone receptor in the hamster was 17β-estradiol= estrone> estriol> 17α- ...
Our previous studies demonstrated a specific progesterone receptor in the estrogen-induced and -d... more Our previous studies demonstrated a specific progesterone receptor in the estrogen-induced and -dependent hamster renal carcinoma and provided evidence that estrogen treatment induces a 4S progesterone-binding component in renal cytosol of the hamster. This latter finding ...
ESTROGENS have been implicated as causative agents in tumor development for more than half a cent... more ESTROGENS have been implicated as causative agents in tumor development for more than half a century. A number of mammalian species, including primates as well as man, are susceptible to the formation of neoplasms, both benign and malignant, at various organ sites after ...
The activity of microsomal estrogen 2-/4-hydroxylase enzyme (ESH), which mediates the formation o... more The activity of microsomal estrogen 2-/4-hydroxylase enzyme (ESH), which mediates the formation of catechol estrogens, was determined in the hamster kidney and liver under different endocrine states and after treatment with diethylstilbestrol (DES) and 5 alpha-dihydrotestosterone alone or in combination. Our results indicate that at least 64% of the renal ESH activity is localized in the kidney cortex. Employing either estrone or 17 beta-estradiol as substrate, a significant decline in renal ESH activity was observed after castration, with estrone remaining the more active substrate. In contrast, hepatic ESH activity, which is about 2.0- to 2.5-fold higher than the kidney enzyme, was not altered after gonadectomy using either estrogen substrate. A further reduction in renal ESH activity was found in DES-treated castrated hamsters when estrone was used. Androgen treatment resulted in a nearly 2-fold increase in kidney ESH activity using either estrogen substrate. Animals treated concomitantly with DES and 5 alpha-dihydrotestosterone exhibited catechol estrogen formation similar to untreated castrate hamster kidney microsomes. In contrast, hamster liver ESH activity was unaffected by androgen treatment. HPLC profiles of the catechol estrogen monomethyl ethers confirm these changes. Hamster kidney ESH activity in females was only 5-7% of that in intact males. Ovariectomy resulted in a 3-fold increase in the activity of this microsomal enzyme with either estrogen substrate. ESH activity was substantially increased in uteri of intact animals after androgen treatment. These data clearly demonstrate that ESH activity is under androgen control, particularly in the hamster kidney of both sexes, and may be pertinent in understanding the antagonism of this hormone in estrogen-induced renal tumorigenesis.
Comparison of the soluble estradiol receptor proteins in the hypothalamus and uterus of the golde... more Comparison of the soluble estradiol receptor proteins in the hypothalamus and uterus of the golden Syrian hamster revealed that both have sedimentation coefficients of 8S in a low ionic strength buffer and migrate similarly on analytical disc-gel electrophoresis in both 5% and 7% acrylamide gels. The competition of [3H]-17beta-estradiol binding by unlabeled estrogenic as well as nonestrogenic compounds was similar with the receptors present in the two tissues. The affinity constants for the hypothalamic and uterine receptors were 4.3 X 10-9M-1 and 1.6 X 10-10M-1, respectively; the number of binding sites when expressed on an equivalent protein basis (i.e. 1 mg/ml) was 0.18 X 10-10M and 3.1 X 10-10M, respectively. Identical amounts of soluble receptors with similar sedimentation characteristics were found in hypothalami from male and female animals gonadectomized 64 h prior to use. A titration of binding sites in the uteri of intact and ovariectomized animals revealed decreased binding in the supernatant preparation from intact animals, probably due to the presence of bound endogenous unlabeled hormone.
A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclin... more A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclins D1 and D3 was examined during estradiol-17beta (E(2))-induced mammary tumorigenesis in female August Copenhagen Irish (ACI) rats. Low serum E(2) levels ( approximately 60-120 pg/ml) were sufficient to induce mammary gland tumors (MGTs) that remarkably resemble human ductal breast cancer (BC) at the histopathologic and molecular levels. Western blot analysis of the E(2)-induced MGTs revealed a marked rise in cyclins D1 (24-fold), D3 (9-fold) and cdk4 (3-fold) expression compared with age-matched untreated controls. Small focal dysplasias with large, pale staining nuclei were commonly seen at 3-3.6 months, large focal dysplasias, including atypical ductal hyperplasia at 3.6-4.3 months, ductal carcinoma in-situ (DCISs) at 4.3-5.0 months, and 100% incidence of invasive ductal BC/frank tumors at 5-6 months were detected after E(2) treatment. Immunohistochemical analysis of serial sections of focal dysplasias, DCISs and invasive ductal carcinomas showed overexpression of cyclins D1, D3, estrogen receptor-alpha (ERalpha) and progesterone receptor (PR). However, cyclin D3 expression, unlike D1, was confined essentially to early pre-malignant lesions (focal dysplasias and DCISs) and primary MGTs with <1-5% of resting and normal hyperplastic breast cells staining positive. The kinase activity for cyclins D1 and D3, using retinoblastoma (Rb) as a substrate, in E(2)-induced MGTs and their binding to cdk4 was significantly elevated. Semi-quantitative reverse transcriptase PCR analysis of the E(2)-induced MGTs exhibited increased expression of cyclins D1 (2.9-fold) and D3 (1.4-fold) mRNA, indicating that their elevated protein expression was due in part to an increase in mRNA transcription. However, when analyzed by quantitative real-time Q-PCR, these genes were not amplified. These data indicate that in female ACI rat mammary glands, E(2)-induced pre-malignant lesions differentially and selectively express cyclins D1 and D3, thus contributing to a distinct growth advantage of these pre-neoplasias relative to E(2)-elicited normal hyperplasia.
An estrogen receptor-driven, multistep process for estrogen carcino- genesis in the Syrian hamste... more An estrogen receptor-driven, multistep process for estrogen carcino- genesis in the Syrian hamster kidney is proposed. Because in this species the reproductive and urogenital tracts arise from the same embryonic germinal ridge, it is evident that the kidney has carried over genes that are responsive to estrogens. Using in situ hybridization, overexpression of early estrogen-response genes, i.e., c-myc and c-fos,
Uploads
Papers by Sara Antonia Li