Hormones and Cancer

, Volume 8, Issue 3, pp 135–142

A Novel Strategy to Co-target Estrogen Receptor and Nuclear Factor κB Pathways with Hybrid Drugs for Breast Cancer Therapy

Original Paper


Nearly 75% of breast tumors express estrogen receptor (ER), and will be treated with endocrine therapy, such as selective estrogen receptor modulator (SERM), tamoxifen, or aromatase inhibitors. Despite their proven success, as many as 40–50% of ER+ tumors fail to respond to endocrine therapy and eventually recur as aggressive, metastatic cancers. Therefore, preventing and/or overcoming endocrine resistance in ER+ tumors remains a major clinical challenge. Deregulation or activation of the nuclear factor κB (NFκB) pathway has been implicated in endocrine resistance and poor patient outcome in ER+ tumors. As a consequence, one option to improve on existing anti-cancer treatment regimens may be to introduce additional anti-NFκB activity to endocrine therapy drugs. Our approach was to design and test SERM-fumarate co-targeting hybrid drugs capable of simultaneously inhibiting both ER, via the SERM, raloxifene, and the NFκB pathway, via fumarate, in breast cancer cells. We find that the hybrid drugs display improved anti-NFκB pathway inhibition compared to either raloxifene or fumarate. Despite some loss in potency against the ER pathway, these hybrid drugs maintain anti-proliferative activity in ER+ breast cancer cells. Furthermore, these drugs prevent clonogenic growth and mammosphere formation of ER+ breast cancer cells. As a proof-of-principle, the simultaneous inhibition of ER and NFκB via a single bifunctional hybrid drug may represent a viable approach to improve the anti-inflammatory activity and prevent therapy resistance of ER-targeted anti-cancer drugs.


Breast cancer Estrogen receptor NFκB pathway Co-targeting drugs 

Supplementary material

12672_2017_294_MOESM1_ESM.pptx (106 kb)
Supplemental Figure 1Synthetic scheme for synthesizing Ral-Fum hybrids. (PPTX 106 kb)
12672_2017_294_MOESM2_ESM.pptx (126 kb)
Supplemental Figure 2Raloxifene inhibits ICAM1 gene expression and NFκB-RE activity. (A) MCF-7 cells were treated with various concentrations of drugs for 1 h, followed by TNFα (10 ng/mL) for 2 h to activate the NFκB pathway. mRNA expression of ICAM1 was measured by RT-QPCR. Drug’s inhibitory activity was calculated as % of TNFα alone, which is set to 100%. (B) T47D cells were transfected and treated with raloxifene as described in Fig. 1. (PPTX 126 kb)
12672_2017_294_MOESM3_ESM.pptx (108 kb)
Supplemental Figure 3Ral-Fum 2 inhibits NFκB-RE activity in breast cancer cells. (A) T47D and (B) MDA-MB-231 cells were transfected and treated as described in Fig. 1. (PPTX 108 kb)
12672_2017_294_MOESM4_ESM.pptx (47 kb)
Supplemental Figure 4Raloxifene-Succinate (Ral-Succ) fails to inhibit the NFκB pathway. MCF-7 cells were treated with 10 μM Ral-Succ for 1 h, followed by TNFα (10 ng/mL) for 2 h to activate the NFκB pathway. mRNA expression of ICAM1 was measured by RT-QPCR. (PPTX 46 kb)
12672_2017_294_MOESM5_ESM.pptx (70 kb)
Supplemental Figure 5DMF fails to inhibit ER in breast cancer cells. MCF-7 cells were treated with 10 μM DMF for 1 h, followed by E2. (A) mRNA expression of ER-target genes, pS2 and EGR3, was measured by RT-QPCR. (B) ERE luciferase activity was measured as described in Fig. 4. (PPTX 70 kb)

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Irida Kastrati
    • 1
  • Marton I. Siklos
    • 2
  • Svitlana D. Brovkovych
    • 1
  • Gregory R. J. Thatcher
    • 2
  • Jonna Frasor
    • 1
  1. 1.Department of Physiology and Biophysics, College of MedicineUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of Medicinal Chemistry and Pharmacognosy, College of PharmacyUniversity of Illinois at ChicagoChicagoUSA

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