Myrothamnus flabellifolius selectively targets Triple Negative Breast Cancer in vitro, restoring Tamoxifen Sensitivity through modulation of miRNAs associated with Estrogen Receptors.

Summary. Triple negative breast cancer (TNBC) represents approximately 15-20% of all breast cancer (BC) cases worldwide. Prognosis for this subtype of BC is especially dire due to the absence of Estrogen (ER), Progesterone and Human Epidermal Growth Factor (HER2) receptors, usually targeted by neoadjuvant therapies like Tamoxifen. There is thus a dearth of targeted therapies for TNBC. Myrothamnus flabellifolius (MF), a well-studied South African medicinal herb, has shown significant anticancer activity with minimal effect on normal cells. In this study, we describe the cytotoxic and apoptosis-inducing effect of MF in TNBC with minimal effects on non-malignant breast cells. We also use miRNA profiling, Ingenuity Pathway Analysis (IPA), MTT and immunoblots to characterize the mechanism of action of MF in TNBC. We found deregulation of several oncogenic miRNAs in TNBC post MF treatment and IPA predicted reactivation of the estrogen-mediated s-phase entry, a pathway typically silenced in TNBC. Immunoblots confirmed restoration of ERα expression and repression of ERs. This increase in ERα/ERs ratio re-sensitized TNBC to tamoxifen treatment. Restoration of let-7i expression, a miRNA severely downregulated by MF, also partially reversed the sensitization effect. This is a preliminary investigation and the results from this studies merits further investigation into the active anti-TNBC compound present in the MF extract. Industrial relevance. The results of our work establish Myrothamnus flabellifolius as potential source for anti-TNBC agents. With increased interest in identifying natural agents that target TNBC, specifically, with minimal effects on neighbouring non-malignant tissue, MF’s dual action of both targeting and re-sensitizing TNBC to hormonal therapy presents a peculiarly interesting therapeutic approach. Our work also presents a case for ER-related miRNAs as drug targets, to restore hormone-therapy sensitivity in the especially troublesome TNBC. Keywords. Triple Negative Breast Cancer; Myrothamnus flabellifolius ; MicroRNAs ; Hormone therapy Normal 0 false false false EN-US JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Cambria",serif; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin;}