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Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors
- Source :
- Breast Cancer Research : BCR
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
Abstract
- Introduction Of the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors. Methods ER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors. Results Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues. Conclusions The studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.
- Subjects :
- ER/PR-negative breast cancers
tumor promoter and suppressor hormones
3α-dihydroprogesterone
Estrogen receptor
Mice, SCID
Tumor initiation
chemistry.chemical_compound
Breast cancer
0302 clinical medicine
Mice, Inbred NOD
Tissue Distribution
Progesterone Receptor Negative
normalcy
Medicine(all)
0303 health sciences
5-alpha-Dihydroprogesterone
20-alpha-Dihydroprogesterone
Tumor Burden
3. Good health
Receptors, Estrogen
progesterone metabolites
Hormone receptor
030220 oncology & carcinogenesis
5α-dihydroprogesterone
Female
Receptors, Progesterone
Research Article
medicine.medical_specialty
Antineoplastic Agents, Hormonal
medicine.drug_class
Breast Neoplasms
03 medical and health sciences
Cell Line, Tumor
Internal medicine
medicine
Animals
Humans
Cell Proliferation
030304 developmental biology
business.industry
biomarkers
5α-Dihydroprogesterone
medicine.disease
Xenograft Model Antitumor Assays
microenvironment
tumorigenesis
Endocrinology
chemistry
Estrogen
hormonal control
business
Hormone
Subjects
Details
- ISSN :
- 1465542X
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research
- Accession number :
- edsair.doi.dedup.....165c462e40dffcea71f5e2092608d154