Triple-Negative Breast Cancer (TNBC) Cell Metastasis is Controlled by the Opposing Actions of 5alpha-dihydroprogesterone (5alphap) and 3alpha-dihydroprogesterone (3alphahp) on Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases
Bibliographic record
Abstract
Abstract BackgroundTriple receptor-negative breast cancers (TNBC) comprise up to 20% of all breast cancers and are the most aggressive mammary cancer subtype, marked by early-onset metastasis, high tumor recurrence rate, and low overall survival. Because TNBC cells lack expression of the estrogen receptor (ER), progesterone receptor (PR) and excess human epidermal growth factor receptor 2 (HER2), there have been no hormone-based explanations and therapeutics for TNBC. Our previous studies had shown that the endogenously produced hormones, 5αdihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, stimulate and inhibit TNBC cell proliferation and primary tumor development. Here we examined the role of 5αP and 3αHP in controlling metastasis of TNBC (MDA-MB-231)human breast cells. The objectives were to determine the effects of 5αP and 3αHP on TNBC cell (a) adhesion, migration and invasion and (b) expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs).MethodsMDA-MB-231 human breast cells were incubated in medium without (control) or with 5αP or 3αHP. Effects on adhesion were examined by previously validated detachment assays. Effects on migration and invasion were measured by transwell assays employing modified Boyden chambers. Effects on expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 were determined by reverse transcription polymerase chain reaction (RT-PCR).Results5αP stimulated, whereas 3αHP suppressed, TNBC cell detachment, migration and invasion. 5αP stimulated expression of MMP-2 and MMP-9, and inhibited expression of TIMP-1 and TIMP-2, whereas 3αHP inhibited expression of MMPs and stimulated expression of TIMPS.ConclusionsHere we show for the first time that 5αP stimulates and 3αHP suppresses the key elements of metastasis (adhesion, migration, invasion) in TNBC cells, and that these opposing actions correlate with the opposing effects of these two hormones on MMP and TIMP expression. The results indicate that the relative concentrations of the cancer-promoter hormone (5αP) and the cancer-suppressor hormone (3αHP) in the breast microenvironment control TNBC cell metastasis, and suggest that blocking 5αP synthesis and increasing 3αHP concentrations in the breast microenvironment could provide the first hormone-based therapeutic regimen to arrest TNBC progression and metastasis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".