A Novel Strategy to Co-target Estrogen Receptor and Nuclear Factor κB Pathways with Hybrid Drugs for Breast Cancer Therapy
- 329 Downloads
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.
KeywordsBreast cancer Estrogen receptor NFκB pathway Co-targeting drugs
IK conceived and coordinated the study, performed and analyzed most of the experiments, and wrote the paper. MIS synthesized the co-targeting agents. SDB performed the luciferase assays. GRJT and JF contributed to the conceptualizing and drafting of the paper. All authors reviewed the results and approved the final version of the manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
This work was supported by grants provided by the National Institute of Health (NIH), R01 CA200669 to JF, and CA121107 to GRJT, and by a postdoctoral fellowship grant from Susan G. Komen for the Cure® to IK (PDF12229484).
- 5.Kubo M, Kanaya N, Petrossian K, Ye J, Warden C, Liu Z, Nishimura R, Osako T, Okido M, Shimada K, Takahashi M, Chu P, Yuan YC, Chen S (2013) Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat). Breast Cancer Res Treat 137:93–107CrossRefPubMedGoogle Scholar
- 18.Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, Cree BA, Sobel RA, Wipke BT, Steinman L, Scannevin RH, Zamvil SS (2016) Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci U S A 113:4777–4782CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Frasor J, El-Shennawy L, Stender JD, Kastrati I (2014) NFkappaB affects estrogen receptor expression and activity in breast cancer through multiple mechanisms. Mol Cell EndocrinolGoogle Scholar
- 24.Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL, Clarke MF (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458:780–783CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Chadwick CC, Chippari S, Matelan E, Borges-Marcucci L, Eckert AM, Keith JC Jr, Albert LM, Leathurby Y, Harris HA, Bhat RA, Ashwell M, Trybulski E, Winneker RC, Adelman SJ, Steffan RJ, Harnish DC (2005) Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity. Proc Natl Acad Sci U S A 102:2543–2548CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Nettles KW, Bruning JB, Gil G, Nowak J, Sharma SK, Hahm JB, Kulp K, Hochberg RB, Zhou H, Katzenellenbogen JA, Katzenellenbogen BS, Kim Y, Joachmiak A, Greene GL (2008) NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nat Chem Biol 4:241–247CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Nwachukwu JC, Srinivasan S, Bruno NE, Parent AA, Hughes TS, Pollock JA, Gjyshi O, Cavett V, Nowak J, Garcia-Ordonez RD, Houtman R, Griffin PR, Kojetin DJ, Katzenellenbogen JA, Conkright MD, Nettles KW (2014) Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. elife 3:e02057CrossRefPubMedPubMedCentralGoogle Scholar