Novel Approaches to Endocrine Therapy in Endocrine-Independent Breast Cancer
Patel, Hitisha K.
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Tamoxifen, an antagonist at estrogen receptor alpha (ERα) in breast tissue, and the prototypical selective estrogen receptor modulator (SERM), is the standard of care for many patients with ER-positive breast cancer. However, continued tamoxifen treatment increases the risk of endometrial cancer and half of ER-positive breast cancer patients do not respond or relapse on treatment with tamoxifen. Tamoxifen-resistant tumors are often ER-positive and endocrine-independent and therefore resistant to aromatase inhibitors. Recent clinical trials have shown the efficacy of estrogen in patients who have undergone exhaustive tamoxifen therapy. Therefore, we propose the development of small molecules that mimic the actions of estradiol in ER-positive breast cancer without the uterotrophic actions of estradiol and tamoxifen: Selective human Estrogen Receptor Partial Agonists (ShERPAs). Evidence suggest that a significant subset of ER-positive breast cancers, over-expressing PKCα, and tamoxifen-resistant cancers will respond to ShERPAs. In order to design and optimize ShERPAs, tamoxifen-resistant cell lines, MCF-7:5C, T47D:A18/PKCα and T47D:A18-Tam1 were studied. The activation of classical ERα signaling by the estrogen mimics was profiled in MCF-7 cells and cell viability in 2D culture was examined. Interestingly, it was found that in MCF-7:5C cells, ShERPA induced cell death was mediated by activation of classical ERα signaling. In an effort to increase throughput and mimic the in vivo environment more closely, we assessed the ShERPAs in a new 3D spheroid model as well. ShERPAs caused decreased spheroid viability in all three models of tamoxifen resistance. Extranuclear localization of ERα after ShERPA treatment was observed. Three promising ShERPAs were evaluated in xenograft models of TAM-resistant, PKCα overexpressing breast cancer. While E2 caused regression of these tumors, a significant increase in uterine weight as predicted was observed. More importantly, ShERPA treated mice had negligible increase in uterine weight underlining the enhanced safety of these molecules. This work suggests that development of ShERPAs that retain the beneficial properties of estrogen while limiting the side effects is a feasible strategy for the treatment of tamoxifen resistant breast cancer.