ABSTRACT
The 40S ribosomal S6 kinase 1 (S6K1) is an important regulator of cell growth. Expression of S6K1 is often elevated in breast cancer cells. However, the transcriptional mechanism of S6K1 overexpression is not understood. In this report, we demonstrate that estrogen activates expression of S6K1 via estrogen receptor (ER)α in ER-positive breast cancer cells. We also show that estrogen acts on the proximal promoter of the S6K1 gene in a mechanism involving the transcriptional factor GATA-3. Finally, we provide data that support the importance of estrogenic regulation of S6K1 expression in breast cancer cell proliferation. S6K1 directly phosphorylates and regulates ligand-independent activity of ERα, while ERα upregulates S6K1 expression. This S6K1-ERα relationship creates a positive feed-forward loop in control of breast cancer cell proliferation. Furthermore, the co-dependent association between S6K1 and ERα may be exploited in the development of targeted breast cancer therapies.
Subject(s)
Breast Neoplasms/pathology , Estrogen Receptor alpha/metabolism , Gene Expression Regulation, Neoplastic , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Proliferation , Estradiol/pharmacology , Estrogen Receptor alpha/genetics , Feedback, Physiological , Female , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/metabolism , Humans , MCF-7 Cells , Mammary Glands, Animal/drug effects , Mammary Glands, Animal/metabolism , Mice , Mice, Inbred Strains , Phosphorylation , Promoter Regions, Genetic , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacologyABSTRACT
Data were collected on 27 patients operated on for bilateral undescended testes. The information included age at operation, reoperations, testis size and location at first operation, testis size in adulthood, sexual behavior and presence of secondary sexual characteristics. The data were related to fertility, as assessed on the basis of spermatograms. A fertility rate of 33.3% was found. The ideal age for operation could not be established, but it was concluded that operation should not be delayed beyond the age of 12 years and that reoperation significantly reduced eventual fertility. It was found that the initial size and location of the testes had no influence on fertility, but that there was a higher rate of infertility in adults with small testes. Despite the high rate of infertility, all patients showed normal sexual development and behavior.
Subject(s)
Cryptorchidism/surgery , Fertility , Sex Characteristics , Sexual Behavior , Testis/surgery , Adolescent , Child , Humans , Infertility, Male/diagnosis , Male , Sperm Count , Sperm Motility , Testis/growth & developmentABSTRACT
PIP: The relationship between excretion of forminoglutamic acid (figlu) in the urine and spontaneous abortion in the first and second trimesters of pregnancy was investigated in 135 nonanemic women after spontaneous abortion and curettage. The 135 were subdivided into Group A, 95 cases with no known reason for spontaneous abortion, and Group B, 40 women in whom probable abortion cause was known; Group C was control. In Group A, figlu was detected in urine of 40 (42.1%). In Group B, where abortion causes ranged from diabetes, to toxoplasmosis, to cervical incompetence, figlu was positive in only 2 (5%) cases. 3/35 controls (8.6%) were positive for figlu. The percentage of positive figlu findings in Group A was significantly higher when compared with Group B (P .001) and with Group C (P .001). In Group A, the positive figlu excretion was statistically unrelated to previous abortions (P .05), previous pregnancies (P .05), or age groups (P .05). Further, when the 40 Group B cases and the 35 Group C cases were compared with the above, there was no change in the results. If increased figlu excretion can be considered an index of folic acid deficiency, then it is possible that this deficiency may be an etiological factor in cases of spontaneous abortion.^ieng
