Biomedical subjects
D T Kiang
Publications and source records attributed to D T Kiang.
Progesterone receptors in feline mammary adenocarcinomas.
Estradiol and progesterone receptors were measured in tumor cytosols from 3 intact and 4 neutered female cats with spontaneously occurring mammary adenocarcinomas. Serum from 2 of the intact cats which had been in estrus 4 and 4 to 6 weeks before tumor excision contained progesterone concentrations of 16.2 and 2.2 ng/ml, respectively; serum progesterone in the other cats was less than 2 ng/ml. Estradiol receptors were not detected in any cytosols. Progesterone receptors were detected in all of the cytosols, in concentrations ranging from 4.0 to 11.7 (mean = 7.2) fmol/mg of protein. Scatchard plot analysis of tumor cytosol from an 8th cat with mammary adenocarcinoma revealed presence of high affinity progesterone binding with a dissociation constant (Kd) of 3.47 nM. Tumor receptor content could not be correlated with stage of the estrous cycle nor with whether the cat was intact or neutered.
Correlation between estrogen-receptor proteins and response to chemotherapy in patients with breast cancer.
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Nuclear estrogen receptor and nonhistone chromosomal proteins in hormonal independency of murine breast cancers.
The capability of nuclear binding of cytosol estrogen receptors (ERc) was studied in GR mouse mammary tumors during their alteration of hormonal dependency through serial transplantations. Nuclei from GR mouse mammary tumors were incubated with uterine cytosol receptor complexes labeled with 125I-estradiol, and the amount of receptor binding in the 0.4 M KCl nuclear extracts was determined. The originally ERc-positive-hormone-dependent (type I) tumors were capable of nuclear receptor binding, while this function was markedly reduced in the evolved hormone-independent (type II) tumors, although the ERc content in the latter was still positive. The originally hormone-independent (ERc-negative, type III) tumors, however, retained the nuclear binding capability. It appears that the hormonal independency in type III tumors is due to a lack of ER, while in type II tumors it may be attributed to the loss of nuclear binding capability for receptor complexes. Nonhistone chromosomal proteins (NHCP) were analyzed by the 2-dimensional gel electrophoretic technique. A Mr 31,000 NHCP was present in 11 of 12 type I, and four of four type III tumors. Following serial transplantation of the type I tumors, this NHCP was either markedly diminished or not observed in all 14 type II tumors examined. Although it coincides with the capability of nuclear receptor binding, the biological function of this NHCP is still undefined and warrants further investigation.
Two classes of estrogen receptors which differ in their activation mechanisms.
Studies on the mechanism of activation of estrogen receptor (ER) have led us to identify two classes of receptors. Effect of molybdate on the activation of ER was determined by their affinity for nuclei or DNA-cellulose. Molybdate caused inhibition of nuclear binding with rat uterine ER, but an increase in the binding was observed with rabbit uterine ER. Similar results were observed when DNA-cellulose was used instead of nuclei. To further test the diversity in ER activation, DNA-cellulose binding of ER from 10 primary breast cancer tissues was determined in the presence or absence of molybdate. ER from 8 tissues showed inhibition of binding, one showed an increase, and one was not affected by molybdate. These results indicate the presence of two classes of ER, one whose activation is inhibited by molybdate and another whose activation is either unaffected or stimulated by molybdate. Other differences between rat and rabbit uterine ER are also discussed.
Cyclic biological expression in mouse mammary tumors.
Biological characteristics were assessed in GR mouse mammary tumors during 22 serial transplantations. Although unidirectional progression from hormone dependency to independency was observed, other biological markers such as progesterone receptors, polyploid frequency and thymidine kinase activity demonstrated cyclic phenomena every fourth to sixth transplant generation, suggesting the continued presence of regulatory mechanisms among various cells subpopulations.
Estrogen receptors in various tissues.
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Metabolism of testosterone by GR mouse mammary tumors.
The metabolism of testosterone by GR mouse mammary tumors following serial transplantation was studied. Oophorectomized female recipients were maintained on estrone and progesterone (OEP) or without hormone maintenance (oophorectomized-only group) in order to assess whether the growth of the tumor was hormone dependent (HD) or hormone independent (HI). Tumors in the early generations of the OEP group were HD (generations 1 to 4), which became HI in the latter generations (G5 to G18). All tumors developed in the oophorectomized-only group (generations 1 to 18) were HI. All tumors investigated were capable of metabolizing testosterone to 4-androstenedione, 16 alpha-hydroxytestosterone, 5 alpha-dihydrotestosterone, 5 alpha-androstanedione, and 5 alpha-androstanediol. Total 5 alpha-reduction in OEP group ranged between 50 and 60% of neutral metabolites in HD tumors and dropped to 13 to 28% in HI tumors (generations 5 to 18), similar to the activities (20 to 30%) of the HI tumors in the oophorectomized only group. Different patterns of estrogen synthesis were observed among these tumors. Although tumors showed the presence of appreciable amounts of estriol, estrone was synthesized only in 5 of the 9 HI tumors in the oophorectomized only group. The most striking contrast was that estradiol was synthesized by all HI tumors in the oophorectomized-only group and the OEP group but not in the HD tumors.
Combination therapy of hormone and cytotoxic agents in advanced breast cancer.
The effectiveness of combination therapy with diethylstilbestrol, cyclophosphamide, and 5-fluorouracil (DES + CTx + FU) was compared with DES alone or CTx + FU in 87 postmenopausal women with advanced breast cancer. Therapy was randomized according to the tumor estrogen-receptor (ER) status. In 30 patients with ER-rich tumors and 35 patients with ER-unknown tumors, combination therapy yielded a higher response rate than DES therapy (87% vs. 64% and 59% vs. 23%, respectively). The pooled data from these two groups of patients suggest that the improved response rate from DES + CTx + FU against DES becomes more apparent in patients with visceral involvement (89% vs. 47%) (P less than 0.025) and that patients treated initially with combination therapy (DES + CTx + FU) appeared to have a longer survival than those treated with sequential therapy (DES leads to CTx + FU) (P = 0.06). The survival data in 22 patients with receptor-poor tumors were significantly inferior to those with receptor-rich tumors (P = 0.001). The ER status and presence of visceral metastases are significant factors in the selection of treatment programs.
Chemoendocrine therapy in advanced breast cancer.
The effect of a combination of endocrine and chemical therapies has been studied during the past decade in DMBA-induced rat mammary tumors and advanced human breast cancers. Although interferential effects have been observed between endocrine therapy and chemotherapy in highly hormone-dependent tumors or cell lines, beneficial effects can be achieved from a combination of these two treatment modalities in human breast cancer when the steroid receptor status and the presence or absence of visceral metastases are considered in the selection of treatment programs.
Feline mammary hypertrophy/fibroadenoma complex: clinical and hormonal aspects.
Abnormal mammary enlargement, characterized microscopically by hyperplasia of both epithelial and mesenchymal tissues, was studied in 26 cats which were mostly young, sexually intact females. Clinicopathologic data indicated that mammary hypertrophy was likely progesterone-dependent. Administration of progestins preceded this condition in 5 cats, 4 of which were neutered. Serum progesterone concentrations (6.7 ng/ml) were increased in 1 of the 3 cats tested. Estrogen receptors were not found in the cytosols or nuclei of mammary tissues in the 2 cats studied. However, there were convincing 4S [3H]progesterone or 5S [3H]R5020 binding peaks which were suppressible by nonlabeled progestins. Progesterone receptors were measured at 14.9 and 8.6 fm/mg of protein, respectively. The apparent influence of progesterone, whether present as exogenous therapy in the male or female or as endogenous steroid of ovarian origin, has thus been demonstrated directly and indirectly in cats with mammary hypertrophy.
Estrogen receptor status and response to chemotherapy in advanced breast cancer.
Tumor estrogen receptor status in women with advanced breast cancer was correlated with clinical response to cytotoxic chemotherapy in a retrospective study. Following an extramural review of the clinical data of 40 patients, 26 responded to chemotherapy (65%). The response rate in 19 receptor-rich tumors was 89% and in 21 receptor-poor tumors, 43% (P < 0.01). The lowest response rate (14%) was observed in seven postmenopausal patients with receptor-poor tumors. Clinical characteristics of patients and variants in chemotherapy programs failed to explain the favorable response of receptor-rich tumors to cytotoxic chemotherapy.
Biological and histological characteristics of simultaneous bilateral breast cancer.
Biological and histological characteristics of simultaneous bilateral breast cancers were studied in 11 patients: 8 had bilateral oestrogen receptor (ER)-positive tumours, 2 had bilateral ER-negative tumours; and only 1 case was asymmetric in receptor status. In contrast 5 of 7 asynchronous bilateral tumours demonstrated disparity in receptor status. The high incidence of bilateral positivity and similarity of receptor content in the simultaneous group suggests that the development of this group of tumours is probably hormonally related. Furthermore, the inverse relationship between tumour size and receptor content suggests an alteration in tumour characteristics during tumour progression.
Comparison of tamoxifen and hypophysectomy in breast cancer treatment.
The effectiveness of hypophysectomy and tamoxifen in treating advanced breast cancer was compared in a randomized study of 26 patients who had responded to prior oophorectomy or additive hormonal therapy. When patients failed to respond or relapsed from tamoxifen or hypophysectomy, the therapy was crossed over. In this designed sequence, the rate and duration of response observed with tamoxifen or hypophysectomy used as the first regimen were comparable. The results suggest that tamoxifen is effective in the posthypophysectomy phase and the sequence or hypophysectomy followed by tamoxifen in hormone-dependent breast cancer is preferable to achieve a maximal control of the disease.
Hormone receptors in breast cancer and response to chemotherapy.
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Estradiol 17 beta-dehydrogenase and estradiol binding in human mammary tumors.
The metabolism of estradiol was studied in 31 human breast carcinoma in vitro. All 16 estrogen-receptor-poor tumors transformed estradiol to estrone with percent conversions ranging from 11.4 to 95 except for one poorly differentiated tumor where 0.5% conversion to estrone was observed. On the contrary, only 3 out of 15 estrogen-receptor-rich tumors showed higher than 10% conversion of estradiol to estrone (p = 0.001). There is indication that the enzymatic activity in receptor-poor tumors steadily decreases in premenopausal patients as they approach menopausal age, whereas, the activity steadily increases in post-menopausal patients as the duration of menopause lengthens.
Aromatization of androgens by human breast cancer.
The metabolism of dehydroepiandrosterone and testosterone by human mammary tumor was investigated. Estrogen synthesis from dehydroepiandrosterone was observed in 9 of 10 estrogen-receptor-negative tumors and only in 2 of 8 receptor-positive tumors (p less than 0.025). Conversion of testosterone to estrogens was observed in 7 of 8 receptor-negative and 2 of 7 receptor-positive tumors. Tumors which are capable of transforming dehydroepiandrosterone to estrogens were also able to aromatize testosterone suggesting that the presence of the aromatase enzyme is inherent to certain tumor cells. No estrogen formation was detected by the mitochondrial-microsomal fraction of normal breast cells while fractions from both fat cell and tumor cell showed estrogen synthesis. Estrogen formation by tumor cell fraction ranged from 5 to 190 times that observed for fat cells. The physiological significance of these results in the neoplastic tissue and its relationship to hormone dependence are discussed.
Metabolism of pregnenolone by human breast cancer. Evidence for 17 alpha-hydroxylase and 17,20-lyase.
The metabolism of 7-(3)H-pregnenolone was studied in vitro using 16 human breast carcinomas. All mammary tumors transformed pregnenolone to progesterone. All estrogen receptor poor tumors and 4 out of 8 estrogen receptor rich tumors converted pregnenolone to 17-hydroxypregnenolone. Five estrogen receptor poor tumors showed the presence of 17,20-lyase as evidenced by formation of dehydroepiandrosterone and androstenedione. In two estrogen receptor poor tumors, conversions of pregnenolone to progesterone, 17-hydroxy pregnenolone, dehydroepiandrosterone, androstenedione and finally to estradiol was documented, providing a hypothetical pathway for steroid metabolism in human breast cancer. The conversion of pregnenolone to 17-hydroxypregnenolone was significantly less in receptor rich tumors and was totally absent in 4 receptor rich tumors with estrogen receptors of over 45 fmol/mg protein.