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Background: Hormone receptor positive, human epidermal growth factor receptor negative Luminal A breast cancer subtype responds to targeted endocrine therapy, signal transduction inhibitors and cyclin dependent kinase inhibitors. Estrogen and progesterone receptor mediated signal transduction involves receptor-DNA binding and transcriptional activation of downstream target genes. In addition to hormone receptor signaling, cellular metabolism of estradiol and progesterone exhibit distinct roles in cancer growth modulation. Targeted therapy is associated with systemic toxicity, therapy resistance and emergence of chemo-resistant cancer initiating stem cells. These limitations emphasize identification of testable drug candidates for therapy resistant breast cancer. Cellular metabolism of ovarian steroid hormones generates oxidative metabolites with distinct growth modulating effects. Anti-proliferative metabolites may represent potential drug candidates.

Objectives: The objectives of the present review are to provide i) Systematic discussion of published evidence relevant to the role of ovarian steroid hormone metabolism in growth modulatory effects on cancer progression, ii) Evidence for applicability of Luminal A breast cancer and drug-resistant cancer stem cell models to identify mechanistic leads for efficacy of anti-proliferative hormone metabolites, and iii) Future research directions for clinical translatability of patient derived preclinical data.

Conclusions: Contrasting growth modulatory effects ovarian steroid hormones, anti-proliferative effects of individual metabolites of ovarian steroid hormones, growth inhibitory efficacy of nutritional herbs via altered cellular metabolism of estradiol and development of drug-resistant cancer stem cell model represent salient features of this review. Collectively, present evidence validates experimental approaches to identify growth inhibitory hormone metabolites and bioactive agent from nutritional herbs as potential drug candidates for therapy-resistant breast cancer.        

Future Research: This review provides a rationale for future investigations to evaluate stem cell targeted efficacy of anti-proliferative hormone metabolites and herbal bioactive agents. These directions may include functional significance of estrogen receptor-β, and telomerase expression. Furthermore, investigations using patient-derived tumor explant and tumor organoid models from therapy-resistant breast cancer may facilitate experimental approaches to expand preclinical evidence for its clinical relevance and translational potential.