This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (for example "sex_steroid_driven_proliferation#Nuclear Steroid Receptor Hyperactivation").
Key tissue-specific substitutions. Endometrium: oestrogen receptor signalling (GO:0030520) unopposed by progesterone, in glandular endometrial epithelium (CL:0002656), giving endometrial hyperplasia. Breast epithelium: oestrogen receptor alpha signalling in luminal epithelium, giving an ER-positive proliferative lesion or carcinoma. Breast stroma: stromal oestrogen signalling with extracellular matrix organisation (GO:0030198), giving a biphasic fibroepithelial lesion. Myometrium: progesterone receptor signalling (GO:0050847) in myometrial cells (CL:0002366), giving a leiomyoma; note this conformer runs on progesterone rather than oestrogen, which is why the amplifier node is written at the nuclear-receptor level rather than as an oestrogen-specific step.
The trigger node is normally realised at the disorder level in the environmental block rather than as a conforming pathophysiology node, because the exposures that drive it (obesity, unopposed oestrogen therapy, tamoxifen, nulliparity, ovulatory cycling) are curated as Environmental entries with influences_mechanisms edges pointing at the conformer's amplifier node.
Not curated as an Xogenesis module. The terminal output is heterogeneous in form across conformers - a diffuse hyperplastic tissue state in endometrium (MPATH:134 hyperplasia) but a discrete benign neoplasm in myometrium and breast stroma (MPATH:218 neoplasm) - so no single pathological-anatomical-entity anchor fits the module, and none is asserted.
The distinction between this module and sustaining_proliferative_signaling is deliberate. That module covers oncogenic growth-signal lesions and constitutive, ligand-independent pathway activation. Here the receptor and its pathway are intact and behaving normally; what is abnormal is the duration and opposition of physiological ligand exposure. A conformer whose receptor has become ligand-independent (for example an ESR1 mutation driving endocrine resistance) has left this module and belongs to that one.
Sustained Sex-Steroid Ligand Exposure
trigger
Prolonged availability of oestrogen or progesterone at the target tissue, without the counter-regulatory signal that normally limits it. The source varies by disorder - repeated ovulatory cycling, peripheral aromatisation of androgens in adipose tissue, an oestrogen-secreting tumour, exogenous unopposed oestrogen, or a selective oestrogen receptor modulator acting as a partial agonist at this particular tissue - but the downstream response converges on receptor hyperactivation.
Downstream
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Nuclear Steroid Receptor Hyperactivation
Sustained ligand availability drives sustained receptor occupancy in the target tissue.
Nuclear Steroid Receptor Hyperactivation
amplifier
Intracellular steroid hormone receptor signalling running above its normal level and for longer than its normal interval. The receptor itself is intact and ligand-dependent; what is abnormal is the duration of activation and the absence of the opposing signal - progesterone in the endometrium, the luteal-phase and post-menopausal fall in ovarian output elsewhere. Which receptor carries the signal is the main tissue-specific substitution: oestrogen receptor in endometrium and breast, progesterone receptor in myometrium.
Two routes reach this node and both are in scope. In the endometrial conformers an excess or unopposed ligand drives an otherwise normal receptor. In the MED12-mutant mesenchymal conformers - breast fibroadenoma and uterine leiomyoma - circulating steroid levels are unremarkable and an intrinsic somatic lesion instead reshapes how the cell responds to them, so the abnormality lies in the transduction rather than in the ligand. Those conformers accordingly carry no ligand-exposure trigger upstream, and a direction-agnostic modifier on the receptor process is appropriate where the published signal is an altered response profile rather than a measured increase.
Downstream
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Sustained Mitogenic Transcriptional Output
The activated receptor acts as a transcription factor at its target promoters.
Sustained Mitogenic Transcriptional Output
central effector
The ligand-bound receptor drives transcription of growth and cell-cycle genes for longer than the physiological interval. Mechanistically this is the rate-limiting, tissue-agnostic step: upstream the ligand source differs by disorder and downstream the lesion differs by tissue, but the mitogenic transcriptional programme is the shared core, which is what makes it the natural key conformance target.
It is not yet the most-used attachment point, and the label should not be read as a claim that it is. Only ER_Positive_Breast_Cancer conforms here today, because that entry curates the transcriptional step as a node of its own. The endometrial and mesenchymal conformers collapse transcription and the proliferation it drives into a single lesion node and therefore attach further downstream. That is a difference in curation granularity rather than a disagreement about the mechanism; an entry that later separates the transcriptional step should attach it here.
Downstream
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Target-Cell Population Expansion
Sustained mitogenic transcription drives cell-cycle entry in the responsive population.
Target-Cell Population Expansion
effector
The hormone-responsive cell population enlarges. Which population expands is the second major tissue-specific substitution - glandular endometrial epithelium, breast luminal epithelium, breast stroma, or myometrial smooth muscle - and in the stromal and myometrial conformers the expansion is accompanied by disordered extracellular matrix deposition (GO:0030198) that gives the resulting lesion its texture.
Used by disorders
Uterine Leiomyoma
as Hormone-Driven Myometrial Smooth Muscle Proliferation and ECM Deposition
Downstream
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Benign Hormone-Dependent Proliferative Lesion
Continued expansion produces a clinically detectable proliferative lesion.
Benign Hormone-Dependent Proliferative Lesion
consequence
A benign proliferative lesion of the target tissue - endometrial hyperplasia, an endometrial polyp, a fibroadenoma, a leiomyoma. This is the usual endpoint of the module and the reason a hormone-responsive tissue finding is more often benign than malignant. The lesion is nonetheless an expanded substrate in which somatic driver alterations can subsequently be selected, so it is also the point at which conforming malignant entries branch away into their own driver nodes. Curators should not read the presence of this node in a cancer entry as implying that progression is the expected course.