ERα-XPO1 crosstalk controls tamoxifen sensitivity in tumors by altering ERK5 cellular localization

Most breast cancer deaths occur in women with recurrent, ERα (+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict risk of endocrine therapy failure, and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies. Using advanced statistical methods, we found that expression levels of several of nuclear transport genes including XPO1 were associated with poor survival and predicted recurrence of tamoxifen-treated breast tumors in human breast cancer gene expression data sets. In mechanistic studies we showed that the expression of XPO1 determined the cellular localization of the key signalling proteins and the response to tamoxifen. We demonstrated that combined targeting of XPO1 and ERα in several tamoxifen resistant cell lines and tumor xenografts with XPO1 inhibitor, Selinexor (SXR) and tamoxifen restored tamoxifen sensitivity and prevented recurrence in vivo. The nuclear transport pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine modulatory reagents and improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role these pathways play in reducing cancer recurrences. Link

Estrogen and Microbiota Crosstalk: Should We Pay Attention?

Recent advances have suggested that steroid hormones such as estrogens, and gut microbiota might synergize to influence obesity, diabetes, and cancer. We discuss recent knowledge of the interactions between estrogens and gut microbiota, and new insights that might offer new approaches to influence this crosstalk and improve metabolic outcomes. Link

Nuclear and extranuclear-initiated estrogen receptor signaling crosstalk and endocrine resistance in breast cancer

Estrogens regulate function of reproductive and non-reproductive tissues in healthy and diseased states including breast cancer. They mainly work through estrogen receptor alpha (ERα) and/or estrogen receptor beta (ERβ). There are various ERα targeting agents that have been used for treatment of ER (+) breast tumors. The impact of direct nuclear activity of ER is very well characterized in ER (+) breast cancers and development and progression of endocrine resistance. Recent studies also suggested important roles for extranuclear-initiated ERα pathways, which would decrease the potency and efficiency of ERα targeting agents. In this mini-review, we will discuss the role of nuclear and extra-nuclear ER signaling and how they relate to therapy resistance in breast cancer. PMID:27394959

Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues

There is great medical need for estrogens with favorable pharmacological profiles that support desirable activities for menopausal women, such as metabolic and vascular protection, but that lack stimulatory activities on the breast and uterus. We report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue–selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained “pathway preferential estrogens” (PaPEs), which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear PaPEs, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily. PMID: 27221711

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

With the advent of the -omics approaches our understanding of the chronic diseases like cancer and metabolic syndrome has improved.
However, effective mining of the information in the large-scale datasets that are obtained from gene expression microarrays, deep sequencing experiments or metabolic profiling is essential to uncover and then effectively target the critical regulators of diseased cell phenotypes. Estrogen Receptor α (ERα) is one of the master transcription factors regulating the gene programs that are important for estrogen responsive breast cancers. In order to understand to role of ERα signaling in breast cancer metabolism we utilized transcriptomic, cistromic and metabolomic data from MCF-7 cells treated with estradiol. In this report we described generation of samples for RNA-Seq, ChIP-Seq and metabolomics experiments and the integrative computational analysis of the obtained data. This approach is useful in delineating novel molecular mechanisms and gene regulatory circuits that are regulated by a particular transcription factor which impacts metabolism of normal or diseased cells.  Zhao, Y.C., Madak Erdogan, Z. Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer. J. Vis. Exp. (109), e53832, doi:10.3791/53832 (2016).

Differential Utilization of Nuclear and Extranuclear Receptor Signaling Pathways in the Actions of Estrogens, SERMs, and a Tissue-Selective Estrogen Complex (TSEC)

Estrogens act through nuclear and extranuclear initiated pathways involving estrogen receptors (ERs) to regulate gene expression and activate protein kinases. We investigated the involvement of extracellular signal-regulated kinase2 (ERK2) and ERα in the activities of estradiol (E2), conjugated estrogens (CEs), selective estrogen receptor modulators (SERMs), and a Tissue-Selective Estrogen Complex (TSEC), a combination of a SERM and CE that has a blended activity. We found that CE and individual CE components were generally less effective than E2 in ERK2 recruitment to chromatin binding sites of E2-regulated genes. Likewise, CE was much less agonistic than E2 in stimulation of proliferation of ERα-positive breast cancer cells. The SERM bazedoxifene (BZA) fully suppressed proliferation stimulated by E2 or CE and reversed gene stimulation by CE or E2, as did the antiestrogen Faslodex. Thus, the balance of biological activities mediated through nuclear ERα vs. ERK2-mediated activities is different for CE vs. E2, with CE showing lower stimulation of kinase activity. Furthermore, at the BZA to CE concentrations in TSEC, BZA antagonized CE stimulation of gene expression and proliferation programs in ERα-positive breast cancer cells. The studies provide molecular underpinnings of the different ways in which SERMs and estrogens support or antagonize one another in regulating the chromatin binding of ERα and ERK2, and modulating gene and cell activities. They illuminate how the combined actions of two classes of ER ligands (SERM and CE, present in TSEC) can achieve unique modes of regulation and efficacy. link