Table 2.

Molecular mechanisms of Tamoxifen resistance in Estrogen receptor-positive breast cancer

Section	Pathway / Molecular Driver	Downstream Effectors / Pathways	Proliferation	Invasion/Metastasis	Apoptosis	EMT	Other Effects	Model / Study Type	Ref.
Growth factors signaling pathways	IGF-II/IGF-IR–c-SRC–EGFR	↑EGFR/MAPK	↑	↑	↓		Estrogen-independent growth	Cell line	[43]
	HER2/AIB1	↑PI3K/AKT, ↑MAPK, ↑ER phosphorylation	↑	↑	↓		Tamoxifen resistance	Clinical/Cell line	[44, 45]
	FGFR1	↑PI3K/AKT, ↑MAPK	↑	↑	↓		↓ER expression, ↑Lymph node metastasis	Clinical/Cell line	[47]
	TGF-β	↑EMT, ↑Proliferation, ↓Apoptosis	↑	↑	↓	↑	Anti-estrogen resistance	Review	[48]
ERα mutations	ERα mutations (e.g. K303R)	↑ER phosphorylation (Ser305), ↑PKA	↑		↓		Tamoxifen partial agonist	Cell line	[49, 51]
PI3K/AKT/mTOR and MAPK pathways	PI3K/AKT/mTOR	↑Survival, ↑Metabolism, ↑Hedgehog	↑	↑	↓		Metabolic reprogramming	Cell line	[59–61]
	Akt/mTOR/HIF-1α	↑Survival, ↑Resistance	↑		↓		Reversed by glycolysis inhibition	Cell line	[62]
	mTOR/CSC	↑CSC survival, ↑Mammosphere formation	↑				Tamoxifen resistance	Patient-derived CSCs	[66]
	Luteolin/MLL3	↑MLL3, ↑H3K4me1, ↓PI3K/AKT/mTOR	↓		↑		Apoptosis, Sensitization	Cell line	[68]
	MAPK/ERRγ	↑ERRγ	↑		↓		Tamoxifen resistance	Cell line	[69]
	SPRED2/MAPK	↑MAPK	↑		↓		Tamoxifen resistance	Cell line	[70]
Dysregulation of apoptotic and autophagic processes	LDHA/Beclin-1	↑Autophagy, ↓Apoptosis, ↑EMT	↑	↑	↓	↑	Reversed by LDHA inhibition	Cell line	[77]
	GPR30/HMGB1	↑HMGB1, ↑Autophagy (via MEK/ERK)	↑		↓		Tamoxifen resistance	CAFs/Cell line	[78]
	ATP6AP1/V-ATPase	↑Lysosomal acidification, ↑Autophagy	↑		↓		Poor prognosis	Cell line	[79]
	Bcl-2/c-Myc/p21	↓Apoptosis	↑		↓		HDAC inhibitors restore sensitivity	Cell line	[80]
	PKC/ERK	↓Apoptosis	↑		↓		Tamoxifen resistance	Cell line	[81]
	Survivin	↓Apoptosis	↑		↓		Statins sensitize to tamoxifen	Cell line	[82]