Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), 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 the 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 signaling 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 the XPO1 inhibitor, Selinexor, 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.
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.
Currently, around 75% of patients with breast tumors test positive for estrogen receptor alpha (ERa) and are treated with endocrine therapies, such as tamoxifen. One-third of the breast tumors eventually become refractory, reducing the survival rate for affected patients. A combination of alternative endocrine therapies and kinase inhibitors is currently used in such patients. However, after an initial period of therapy response, these tumors relapse in a more aggressive form. Further, the alternative therapies are not optimal in terms of pharmacological properties, are poorly tolerated, and have side-effects that severely decrease quality of life of the patient. Thus, there is a critical need for novel, targetable, mechanism-based therapeutic strategies that 1) re-sensitize ERa (+) tumors to endocrine therapies, and 2) include diagnostic methods to select patients likely to benefit from this approach. Our objective in this study is to validate a group of nuclear transport genes as biomarkers for endocrine resistance, and to evaluate their inhibition as a novel means to enhance the effectiveness of endocrine therapies. Our central hypothesis is that high expression of these genes in ERa (+) tumors serve as a viable biomarker for risk of endocrine therapy failure. We focused on XPO1, the main nuclear export protein, which exports ERK5 from the nucleus to the cytoplasm and we used selinexor (KPT-330), the inhibitor of XPO1, which is already used in clinical trials for solid and hematological cancers (clinicalTrials.gov). Our experiments show that estradiol induces nuclear localization of ERK5, which otherwise would contribute to increased invasiveness and metastatic potential in the cytoplasm. Selinexor increases ERK5 nuclear localization in tamoxifen resistant breast cancer cell lines. Our hypothesis is that sequestering ERK5 in the cell nucleus and blocking its recycle into the nucleus by selinexor is directly associated with the improved transcriptional response to endocrine therapies. The nuclear export 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 reagents and improving therapy response of relapsed ERa(+) tumors, our findings show high and significant promise for uncovering the role of these pathways and demonstrating their use in reducing cancer recurrences. Citation Format: Eylem Kulkoyluoglu, Kinga Wrobel, Yiru Chen Zhao, Karen L. Chen, Kadriye Hieronymi, Jamie Holloway, Yosef Landesman, Tania Ray, Partha S. Ray, Alexander E. Lipka, Rebecca L. Smith, Zeynep Madak Erdogan. Targeting nuclear transport pathways to overcome endocrine resistance and recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1812.
Obesity is a preventable risk factor for post-menopausal ERα-(+) breast cancer. We hypothesized that serum from obese post-menopausal women contain factors that would increase tumorigenicity of breast cancer cells and increase risk of ERα-(+) breast cancer. Using whole metabolite profiling and OLINK biomarker panel of about 400 proteins associated with cancer, inflammation and cardiovascular disease, we identified biomarkers that were differentially present in serum from 50 obese v.s. 50 non-obese postmenopausal women. Next, using in vitro cell based assays as proxy we identified certain free fatty acids (FFAs) as factors from serum that correlate with increased cell proliferation, motility and mTOR activation in ERα(+) breast cancer cells. We performed RNA-Seq, ERα ChIP-Seq and metabolomics analysis in breast cancer cells that are exposed to conditions that mimic serum from obese postmenopausal women. This integrative -omics approach enabled us to uncover ERα and mTOR pathway-dependent metabolic rewiring in breast cancer cells under these conditions. Pathway preferential estrogens (PaPEs), which target ERα and mTOR signaling, were able to block free fatty acid-dependent proliferation of breast cancer cells. In fact, efficient cancer cell killing by PaPEs was achieved only in the presence of FFAs, suggesting a role for obesity-associated metabolic rewiring in providing new vulnerabilities for the breast cancer cells. In summary, we uncovered a novel role for extranuclear-initiated ERα signaling in rewiring breast cancer cell metabolism in response to obesity-associated factors in the serum. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would exploit new metabolic vulnerabilities of breast tumors in obese postmenopausal women. Citation Format: Zeynep Madak Erdogan, Yiru C. Zhao, Gianluigi Rossi, Kinga Wrobel, Eylem Kulkoyluoglu, Sung Hoon Kim, John A. Katzenellenbogen, Jodi Flaws, Rebecca Smith. Extranuclear ERα-mTOR signaling rewires cancer cell metabolism during obesity-associated breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1003. doi:10.1158/1538-7445.AM2017-1003
The majority of breast cancer-specific deaths occur in women with recurrent, ERα (+), metastatic tumors that are initially responsive to endocrine therapy yet become endocrine-resistant. There is a critical need for novel therapeutic approaches to re-sensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignal Finder pathway profiling, Seahorse metabolic profiling and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tamoxifen (4-OH-Tam) and Selinexor (SXR), a highly selective XPO1 inhibitor that is currently in clinical trials for leukemia and prostate cancer, inhibited Akt phosphorylation by changing the phosphorylation status and localization of the kinase. Since we observed dramatic changes in Akt activity, we hypothesized that metabolic pathways and consequently metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and induce autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for combined targeting of ERα and XPO1 in the clinic to reduce cancer recurrences. Citation Format: Madak Erdogan Z, Kulkoyluoglu E. Combined estrogen receptor alpha and XPO1 targeting to overcome endocrine resistance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-13.
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