Though unnecessary for life itself, androgens are essential for the propagation of the species and for establishment and maintenance of the quality of life of males through their support of sexual behavior and function, muscle strength, and sense of well-being. In carrying out its many functions, T acts both as hormone and prohormone. It is an outstanding example of the diverse evolutionary utilization of a primitive informational molecule both among and within species. Not only does T act through the androgen receptor both unchanged and via 5 alpha-reduction, but it acts in tissues with a high aromatase level as an estrogen via the estrogen receptor. Furthermore, DHT, binding to the estrogen receptor, can act as an inhibitor of estrogen action. The products of androgen metabolism may also play active regulatory roles in hematopoiesis and in the regulation of certain hepatic enzymes. Table 3 summarizes the actions of secreted T in males indicating the probable effector hormone. While gross hypogonadism is uncommon, mild androgen insufficiency may be much more frequent, especially in older men, and in those receiving treatment for chronic medical conditions. It is quite possible that such individuals would benefit from appropriate androgen therapy were it available, but the current forms of replacement therapy are not very satisfactory. Better approaches are required. With the exception of a small number of secreted proteins, the products of transcription induced by androgens are not, as yet, known. When the androgen receptor gene is cloned it will be possible to identify androgen-regulated genes and their products. It will then be possible to design agents selectively producing specific desired androgenic effects.

Biological actions of androgens

Cytochrome P450 enzymes that metabolize estrogens are expressed in the mammary gland, uterus, brain and other target tissues for estrogen action, and this results in the formation of hydroxylated estrogens in these tissues. Estradiol metabolites formed in target tissues at or near estrogen receptors may either be inactive or have important biological effects, and changes in the activities of estrogen-metabolizing enzymes in target tissues may profoundly influence estrogen action. Although some active estrogen metabolites exert hormonal effects in target tissues by interaction with the classical estrogen receptor, other metabolites appear to elicit unique biological responses that are not associated with activation of this receptor. Therefore, some of the many actions of estradiol may not be caused by estradiol per se, but may result from the formation of active estrogen metabolite(s) which function as local mediators or may activate their own unique receptors or effectors. This is an important area in need of more research. The present paper represents a review of the literature and perspectives by the authors on the functional role of estrogen metabolism in target tissues.

https://www.hormonebalance.org/images/documents/Zhu%2098estrogen%20metabolism%20in%20target%20cells%20Carc.pdf

Functional role of estrogen metabolism in target cells: review and perspectives.

Transcriptional activation and nuclear targeting signals of the human androgen receptor

The prostasome: its secretion and function in man.

In this report, we describe a novel cDNA isolated from a primary human breast adenocarcinoma and differentially expressed in several breast carcinoma cell lines. The protein encoded by this cDNA, which we have named mammaglobin, is homologous to a family of secreted proteins that includes rat prostatic steroid-binding protein subunit C3, human Clara cell 10-kilodalton protein, and rabbit uteroglobin. Expression of the mammaglobin gene is restricted to the adult mammary gland. More significantly, in an analysis of 35 breast tumor biopsies, mammaglobin mRNA levels were increased at least 10-fold relative to normal breast tissue in 23% of cases. The breast-specific expression of this potentially secreted protein and its frequent overexpression in primary human breast tumors suggest that mammaglobin may be a novel marker for the management of breast cancer.

/pdf/mammaglobin-a-mammary-specific-member-of-the-uteroglobin-4iy6heh5qg.pdf

Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer.

Molybdate-stabilized androgen receptors have been quantitated in cytosols derived from 1026 malignant breast tumors including all new cases of primary breast cancer reported in the western region of Norway during the 3-year period 1985-1987. A simple single point saturation assay using the synthetic labeled ligand methyltrienolone was evaluated for this purpose. This approach also allowed the simultaneous determination of estrogen and progesterone receptor from the same cytosol preparation. The cytosol content of albumin was also recorded in order to control for dilution by extracellular proteins. Androgen receptor was the sex hormone receptor most frequently found both in primary and secondary breast cancer. In primary tumors 84.9% (723 of 852) showed a cytosol concentration higher than 10 fmol/mg protein compared to 71.2 and 67.1% for estrogen and progesterone receptors, respectively. This incidence is about 2 times higher than previously reported for androgen receptors in the literature and may be due to the stabilizing effects of molybdate and a serine protease inhibitor on the recovery of active binding sites in cytosol. Cytosol concentration of androgen receptor is generally lower than that of the other sex hormone receptors; the average level was 65.5 fmol/mg cytosol protein compared to 86.8 and 84.7 for estrogen and progesterone receptors, respectively. Both incidence and cytosol concentrations were lower for all sex hormone receptors in soft tissue metastasis than in the primary tumor. This decrease is not likely to be due to differences in tumor cellularity since metastatic tumors appear to be more cellular as judged from a lower cytosol content of extracellular proteins (albumin). No significant differences were observed in any parameter investigated between different metastatic sites (skin, lymph nodes). Androgen receptor levels were strongly correlated to estrogen and progesterone receptor concentration in both primary and secondary cancers. Cytosol androgen receptor concentration increases with age. This increase is more significant in metastatic than in primary tumors. Evidently, tumor cellularity is a confounding factor in primary tumors since tumor cytosols from younger patients showed a higher content of extracellular proteins. Receptor levels in lymph node metastasis did not exhibit age dependence. This may suggest that locally produced factors rather than circulating levels of sex steroids modulate tumor receptor expression. In metastatic tissues androgen receptors are present with twice the frequency of progesterone receptors and one in four of these tumors express androgen receptor as their sole sex hormone receptor. This supports the view that some of the beneficial effects of high dose progestin treatment of advanced breast cancer are mediated through the androgen receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

https://cancerres.aacrjournals.org/content/canres/49/24_Part_1/7162.full.pdf

Improved measurement of androgen receptors in human breast cancer.

Prostatein. A major secretory protein of the rat ventral prostate.

Binding properties of progesterone-binding Cyst protein, PBCP.

Breast tumor cytosol has been analyzed for the presence of a progesterone-binding protein (PBCP), commonly present in benign breast cysts in huge concentrations. In 377 primary carcinomas investigated PBCP was present in measurable quantities in 60.7% using “rocket” immuno-electrophoresis. Concentrations of PBCP ranged from 0 to 12.4% of total cytosol protein with an average of 4.0 µg/mg cytosol protein. The distribution of PBCP values seems to suggest two tumor populations, one of which is lacking in PBCP and the other showing a lognormal distribution. In malignant tumors PBCP levels were negatively correlated ( P = 0.024) to estrogen receptor but not to ( P = 0.38) progestin receptor levels. There was a highly significant ( P < 0.001) positive correlation to cytosol albumin concentration which suggests an extracellular localization of PBCP possibly caused by restricted lymphatic drainage of tumor tissue. In benign breast tumors, mainly fibroadenomas, both PBCP incidence (81%) and average concentration (13.5 µg/mg protein) was higher than in malignant tumors. A positive correlation to sex-hormone receptor levels were observed indicating that PBCP production could be under hormonal control in this type of tumor development. In 71 metastatic tumors examined PBCP incidence was far less than in primary tumors ( P < 0.001) and the levels seen were also considerably lower. PBCP holds promise as a marker of tumors in an early stage of development and/or with a low metastatic potential.

https://cancerres.aacrjournals.org/content/canres/47/23/6189.full.pdf

Progesterone-binding Cyst Protein in Human Breast Tumor Cytosol

Albumin content has been reported to be significantly different in cytosols from benign and malignant breast tumors, with a higher level in benign lesions. Low albumin content is suggested to be associated with a higher tendency to axillary nodal involvement in breast cancer patients. Albumin contributes greatly to the total amount of protein in tumor cytosol, and is easily measured. Albumin was measured in cytosols from 382 patients with breast cancer stage I and II, to evaluate correlations to other tumor variables and to investigate whether it may add information as a prognostic factor. The albumin content was expressed in percentages of total cytosol protein, with a median value of 18.5% for the study population. It was found to be significantly inversely correlated to estrogen receptor (ER) content. Cytosol protein content was inversely correlated to albumin. In addition to tumor size and axillary nodal involvement, albumin content was found to be an independent prognostic factor for relapse-free sur...

Oscar A. Lea

Papers

Improved measurement of androgen receptors in human breast cancer.

Prostatein. A major secretory protein of the rat ventral prostate.

Binding properties of progesterone-binding Cyst protein, PBCP.

Progesterone-binding Cyst Protein in Human Breast Tumor Cytosol

Cytosol Albumin Content in Operable Breast Cancer Correlations to Steroid Hormone Receptors, Other Prognostic Factors and Prognosis