Abstract::Breast cancer remains a major public health challenge in India, with rising
incidence and the limited efficacy of conventional chemotherapeutics driven by
multidrug resistance (MDR), systemic toxicity, and therapeutic relapse. This review
synthesizes emerging mechanistic evidence on repurposed synthetic agents and
bioactive natural compounds, presenting a unified framework for mechanism-guided
anti-cancer intervention. The selective estrogen receptor modulator (SERM)
ormeloxifene exemplifies the promise of drug repurposing, exerting multi-target
cytotoxicity through mitochondrial membrane depolarization, G0/G1 cell-cycle arrest,
caspase-dependent apoptosis, ERα modulation, and disruption of proliferative
signaling circuits. In parallel, potent natural products—including ellagitannins (corilagin,
castalin, punicalagin) and triterpenoid saponins (α-hederin, D-rhamnose-β-hederin,
quillaic acid, hederagenin)—demonstrate complementary mechanisms by enhancing
intracellular ROS accumulation, suppressing PI3K/Akt and mTOR signaling, inhibiting
NF-κB activation, and triggering intrinsic and extrinsic apoptotic pathways. Integrating
these mechanistic axes, this review highlights a key innovation: both synthetic and
phytochemical scaffolds converge on actionable molecular nodes governing survival
signaling, metabolic rewiring, and MDR modulation. This convergence underscores
their translational potential for developing combination or sequential regimens that
enhance selectivity, circumvent drug resistance, and minimize off-target toxicity.
Collectively, these mechanistically validated agents represent promising leads for
preclinical optimization and rational design of next-generation, pathway-directed breast
cancer therapeutics.