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.
Show evidence (1 reference)
"During each ovulatory cycle, the myometrium responds to the ovarian steroids, estradiol, and progesterone, via increased tissue stem cell proliferation to prepare for impending pregnancy, during which a somatic mutation may arise to initiate a tumor."
Describes repeated physiological steroid exposure driving a proliferative response in the target tissue, and the somatic mutation arising on that proliferative substrate. Evidence source is OTHER because this is a Physiological Reviews synthesis spanning human, animal and in vitro work.
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.
Show evidence (2 references)
"At the heart of this subtype is the estrogen signaling pathway, especially the estrogen receptor alpha (ERα), which plays a major role in the development, growth, and response to these cancers."
Places receptor-level oestrogen signalling at the centre of the hormone-dependent breast phenotype, supporting this node as the amplifier in the breast conformer. Evidence source is OTHER because this is a narrative review spanning mechanism and therapeutics.
"Conditions that are accompanied by prolonged progesterone deficiencies therefore promote endometrial proliferation and increase the risk of endometrial hyperplasia and its progression to endometrial cancer"
Establishes that it is the loss of progesterone opposition, not oestrogen alone, that makes the signal pathological in the endometrial conformer - the "unopposed" half of this node.
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.
Show evidence (1 reference)
"Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo."
States the conserved mitogenic step across multiple hormone-responsive target tissues, which is what makes this a module node rather than a disorder-specific one. Evidence source is OTHER because the review explicitly synthesises in vitro and in vivo evidence.
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.
Downstream
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Benign Hormone-Dependent Proliferative Lesion
Continued expansion produces a clinically detectable proliferative lesion.
Show evidence (1 reference)
"the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo"
Supports proliferation of the target-tissue cell population as the measured consequence of the hormonal signal, across more than one tissue.
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.
Show evidence (2 references)
"In asymptomatic women, the risk of malignancy is low, and there are no known benefits of polyp removal in the prevention of malignant transformation."
Supports the benign lesion usually remaining benign, which is the claim that distinguishes this consequence node from a precursor node on an obligate path to malignancy.
"The most common etiology of PMB is vaginal or endometrial atrophy and endometrial polyps, while endometrial hyperplasia and carcinoma account for less than 10% of PMB."
Quantifies the benign preponderance in the endometrial conformer, where benign lesions outnumber hyperplasia and carcinoma among women presenting with the cardinal symptom.
Steroid Hormone Axis Suppression
Platform:
Small molecule
Lowering ligand availability or blocking the receptor - aromatase inhibition, GnRH agonist or antagonist therapy, or a receptor antagonist - acts on the amplifier node rather than on the downstream lesion. This is the module's drug-target design pattern: because the lesion is hormone-dependent, withdrawing the signal shrinks it, and the effect is typically reversible on withdrawal, which is itself evidence that the amplifier is the operative node.
Evidence: 1
Progestin Opposition of the Target Tissue
Platform:
Small molecule
Supplying the counter-regulatory signal the module lacks, rather than removing the driving one. In the endometrium local progestin delivery restores the opposition whose absence defines the amplifier node, and largely prevents the benign lesion from forming. Its efficacy is the cleanest evidence that the endometrial conformer runs through an opposable oestrogen-receptor route.
Evidence: 1