About

Benita S. Katzenellenbogen is a Swanlund Professor of Molecular & Integrative Physiology and Cell & Developmental Biology at the University of Illinois. Her research focuses on the regulation of gene expression, signal transduction, and cell proliferation and phenotypic properties by hormones and growth factors. She conducts functional analyses of nuclear hormone receptors, particularly estrogen and progesterone receptors, and their genome-wide activities. Her work involves understanding the mechanisms of hormone and antihormone action in normal and cancer cells, especially in breast cancer, and identifying biomarkers related to therapeutic resistance. Her studies include detailed biochemical and structure-function analyses of receptors and coregulators, genome-wide analyses of receptor and transcription factor cistromes and transcriptomes, and examining the cross-talk between nuclear hormone receptors and cell signaling pathways. She investigates how these receptors regulate gene expression and cell growth, with a particular emphasis on breast cancer, reproductive biology, and fertility. Katzenellenbogen's contributions have advanced understanding of hormone receptor biochemistry, receptor mutations in therapy resistance, and the development of targeted therapies, including selective estrogen receptor degraders and antiestrogens. Her work has significant implications for cancer treatment, endocrine sensitivity, and reproductive health.

Research topics

• Biology
• Cancer research
• Medicine
• Internal medicine
• Endocrinology
• Cell biology
• Genetics
• Oncology
• Immunology
• Biochemistry

Selected publications

• Estrogen Receptor Mutants with Endocrine Therapies Stabilize Multiple Receptor Antagonist Substates to Drive Efficacy and Resistance

  Endocrinology · 2025-04-01

  articleOpen access

  Abstract Text Current endocrine therapies for breast cancer are used to treat the 70 percent of estrogen receptor (ER) positive breast cancers, but de novo and acquired resistance drive progressive metastatic disease. Hormone therapy development efforts have used similar chemical targeting strategies such that the structural basis of ligand efficacy is not clear. More than a third of patients who develop endocrine therapy resistance have hotspot constitutively activating mutations in the ligand binding domain, most notably Y537S and D538G. While these mutants have been studied extensively in stabilizing agonist conformation and constitutive activity in the absence of estradiol, the structural basis for why these mutations cause loss of efficacy for antagonists is not as well studied. To improve our understanding of structural mechanisms of therapeutic efficacy in the ESR1 mutant setting, we synthesized a diverse series of compounds including ∼100 ligands based on a high affinity adamantyl scaffold. We diversified the ligand side chains with various pharmacophores to understand the structural basis of ligand potency and efficacy on wild type and mutant ERs. Crystal structures of 20 ligands bound to Erα-LBD revealed how the chemical side chain modulated receptor structure to stabilize different conformational states to drive anti-cancer activity. Previous work revealed how the ER mutants drive constitutive activity by stabilizing the active ER conformation, but this state does not occur with antagonist bound ER. Long timescale molecular dynamics simulations were used to understand conformational changes induced by these mutations in the context of the antagonist conformation of the key helix 12 (h12), which determines pathogenic versus therapeutic activity states. The Y537S mutation stabilized h12 in one of two stable antagonist substates with implications for generating treatment resistance. In contrast, the D538G mutation, which is characterized by a helix-breaking effect, generated multiple metastable conformational substates. These findings support a model where the ligand side chains alter the relative stability of different antagonist substates to drive efficacy, with conformations that are different in the wild type versus mutant ERα bound to endocrine therapies. Date of Presentation October 17, 2024

  PublisherOA PDFDOI

• Inhibition of FOXM1 Synergizes with BH3 Mimetics Venetoclax and Sonrotoclax in Killing Multiple Myeloma Cells through Repressing MYC Pathway

  Advanced Science · 2025-07-14 · 3 citations

  articleOpen access

  Relapsed and refractory multiple myeloma (RRMM) remains the leading cause of MM mortality. FOXM1 is strongly associated with RRMM, making it a compelling therapeutic target. Through three low-throughput screenings, we have identified nine FDA-approved drugs, including the BH3 mimetic Venetoclax, that synergize with FOXM1 inhibitor NB73 in killing MM cells. Venetoclax has shown effects in 6% of non-t(11;14) and 27% of t(11;14) MM cases. The NB73-Venetoclax combination barely induces acute toxicity in vivo and represses MM cells in vivo and ex vivo. NB73 enhances the ubiquitination and proteasomal degradation of FOXM1, an effect further amplified by Venetoclax. The NB73-Venetoclax combination abolishes FOXM1's binding to promoters of key MYC pathway genes, such as PLK1, leading to significant downregulation of their expression. Furthermore, the PLK1-specific inhibitor GSK461364 synergizes with NB73 to inhibit MM cell growth. Interestingly, NB73 does not sensitize U266 cells, a Venetoclax-resistant t(11;14) MM cell line expressing high FOXM1, to Venetoclax treatment, which is corrected by a new-generation BH3 mimetic Sonrotoclax and ALK inhibitor Ceritinib. Collectively, targeting FOXM1 demonstrates significant potential for enhancing the efficacy of FDA-approved drugs in RRMM. These findings shed new light on the discouraging outcomes of the Phase-III CANOVA study centering Venetoclax with an encouraging molecular clue.

  PublisherDOI

• FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer

  Research Square · 2025-09-30

  preprintOpen access
  PublisherDOI

• FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer

  Research Square · 2025-07-01

  preprintOpen access
  PublisherOA PDFDOI

• Targeting FOXM1 reshapes antitumor immunity to attenuate small cell lung cancer progression

  Cancer Letters · 2025-11-21

  articleOpen access
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• Benzestrol Isomer Stereochemistry Determines the Distinct Estrogenic Activities and Conformations of the Eight Isomers When Bound to Estrogen Receptor α

  ACS Pharmacology & Translational Science · 2025-07-09 · 1 citations

  articleOpen access

  The nonsteroidal estrogen, benzestrol, has potent estrogenic activity, and through a recent stereocontrolled synthesis, we have obtained all eight of its constituent stereoisomers. We find that only one of them, RSS benzestrol, has very high binding affinity for estrogen receptor alpha (ERα); the other seven isomers have 60 to 600-fold lower affinity. We now show that the potencies of the isomers in two cell activity assays, proliferation of ER-positive breast cancer cells and stimulation of estrogenic gene activity, reflect their varying binding affinities for ERα. The crystal structure of the RSS isomer itself is consistent with its presumed absolute configuration and also reveals its conformational flexibility within the solid crystal lattice. We modeled each of the 8 benzestrol stereoisomers bound to ERα. Their calculated binding energies and internal torsional energies grouped with their experimentally measured binding affinities and biological activities, and the conformation for the highest affinity RSS isomer bound to ERα maps closely onto the conformation of the ERα-bound potent nonsteroidal estrogen, trans-diethylstilbestrol. Hence, we now provide a structural context for this congeneric series of benzestrol stereoisomers by proposing energy-based conformations they adopt when bound to ERα that underlie their effectiveness as estrogens.

  PublisherDOI

• Abstract 435: JAK/STAT1-interferon-ISGylation networks in breast cancer resistance to inhibitors of FOXM1 and CDK4/6

  Cancer Research · 2025-04-21

  article1st authorCorresponding

  Abstract Resistance to targeted therapies often develops in advanced estrogen receptor (ER)-positive breast cancer, but the mechanisms underlying this resistance are still not fully known. We show that ER-positive FOXM1 inhibitor resistant cells and CDK4/6 inhibitor (Palbociclib and Abemaciclib) resistant cells all exhibit an increased JAK/STAT1-interferon responsive gene and protein signaling network with elevated interferon stimulated gene15 (ISG15). ISG15 protein is present as high intracellular free ISG15 and also as increased ISGylated protein conjugates that can be markedly reduced by treatment of resistant cells with the JAK1/2 inhibitor ruxolitinib. Likewise, resistant cells contain increased levels of ubiquitin-like conjugating enzymes HERC5 and HERC6 and ubiquitin ligases (e.g., UBE2L6) known to facilitate the transfer of ISG15 onto cell proteins. Notably, elevated ISG15 and elevated HERC5 and HERC6 are all associated with poorer relapse-free and overall patient survival. Breast cancer cells resistant to the CDK4/6 inhibitors Palbo or Abema, which are often used in first line treatment of patients with HR-positive breast cancer, and cells resistant to FOXM1 inhibitor show some similarities in the ISGylated protein patterns. However, there are also some differences observed in these patterns between Palbo and Abema and FOXM1 inhibitor (NB73) resistant cells. Upregulation of this STAT1-interferon-ISGylation network in ER-positive breast cancers displaying resistance to three different drugs suggests it may be centrally involved in supporting the drug-resistant state. Importantly, Palbo and Abema resistant cells and organoids can still be effectively growth inhibited by FOXM1 inhibitor NB73, and likewise, FOXM1 inhibitor resistant cells and organoids are sensitive to suppression of viability by Palbo or Abema. This suggests that sequential treatment approaches might be effective in overcoming resistance and enabling the suppression of these drug-resistant cancers.(Supported by Breast Cancer Research Foundation grant BCRF-083 and NIH R01CA220284 to BSK and BCRF grant BCRF-145 to RS) Citation Format: Benita S. Katzenellenbogen, Yvonne Ziegler, Sandeep Kumar, Blake N. Plotner, Carlos M. Saeh, Grace O. Pento, Sung Hoon Kim, Rachel Schiff, John A. Katzenellenbogen. JAK/STAT1-interferon-ISGylation networks in breast cancer resistance to inhibitors of FOXM1 and CDK4/6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 435.

  PublisherDOI

• OR04-08 Ligand Class Analysis Enables Predictive Models for Effective Antagonism of Endocrine Resistant Breast Cancer

  Journal of the Endocrine Society · 2025-10-01

  articleOpen access

  Abstract Disclosure: J.C. Nwachukwu: None. C.K. Min: None. R.R. Kobylski: None. T.J. Kim: None. Y. Hou: None. S. Kim: None. G.R. Hancock: None. T. Izard: None. S.W. Fanning: None. B.S. Katzenellenbogen: None. J.A. Katzenellenbogen: None. K.W. Nettles: None. Drugs targeting the estrogen receptor-α (ER) fall into two chemical classes, selective estrogen receptor modulators and degraders (SERMs and SERDs), which are effective treatments for hormone-responsive breast cancer. Compounds in these chemical classes typically show similar optimized efficacy in pre-clinical models of breast cancer, including in the context of ER-activating mutations (e.g. ER Y537S) and other resistance pathways, limiting our ability to identify small differences that may be more impactful clinically. To understand structural and molecular drivers of ER antagonism, we expanded the repertoire of ER targeting strategies. We characterized 108 compounds derived from a high-affinity adamantyl scaffold, incorporating 8 distinct classes of pharmacophores, each featuring a diverse array of chemical groups. The chemically diverse ligands revealed that non-canonical targeting approaches produced complex structure activity relationships across a panel of hormone sensitive and resistant breast cancer cell lines and reporter systems, activity that was often more efficacious than existing ER-targeted therapies. We obtained X-ray crystal structures of 25 adamantyl ligands bound to ER resistance mutants. This revealed how the different ligand chemical groups generated diverse structural effects on the surface binding site for transcriptional regulatory proteins that regulate gene expression. Molecular dynamics simulations showed that ER Y537S and D538G stabilized different antagonist conformers, or substates, from the wild type receptor, suggesting a structural basis for resistance to ER antagonists. We selected a subset of 11 adamantyls for a computational approach called “ligand class analysis” (LCA). LCA leverages the wide range of growth inhibitory effects of these related compounds (i.e. a compound class) to provide the statistical robustness for machine learning the underlying mechanisms of action. RNA-seq from MCF-7 cells expressing the ER Y537S resistance allele revealed ∼1600 genes differentially regulated by the 11 adamantyl ligands. We used the growth inhibitory effect of each ligand as the dependent variable in machine learning and identified a gene set response pattern with >95% predictive power for ligand efficacy. Defining causal links from ligand to receptor structure and the cellular mediators of growth inhibition revealed basic principles of allosteric signaling and transcriptional regulation. LCA differentiated these outcome-focused ER signaling pathways from the full set of ligand-regulated cellular effects, while diversification of the ligand-receptor structures identified new ways of modulating ER activity for targeting endocrine resistant breast cancer. Supported by NIH R01CA275142, R01CA220284, R37CA27934, and the Breast Cancer Research Foundation BCRF-083 and BCRF-084 Presentation: Saturday, July 12, 2025

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• Inhibition of FOXM1 synergizes with BCL2 inhibitor Venetoclax in killing non-t(11;14) multiple myeloma cells via repressing MYC pathway

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-28

  preprintOpen access

  Abstract Despite significant improvements in the prognosis of Multiple Myeloma (MM), relapsed/refractory MM remains a major challenge. BCL2 inhibitor Venetoclax induced complete or very good partial responses in 6% of non-t(11;14) MM cases, compared to 27% in t(11;14) cases, when used as monotherapy in relapsed/refractory MM. Though Venetoclax was proposed to treat t(11;14) cases, the resistance became a concern. Furthermore, non-t(11;14) cases account for 80-85% of MM cases, which underscores the value of Venetoclax in non-t(11;14) MM. Here, we report a recently-invented small molecule inhibitor of FOXM1 NB73 synergizing with Venetoclax in killing MM cells. FOXM1, a critical forkhead box transcription factor in high-risk and relapsed/refractory MM, represents a promising therapeutic target of MM. We examined the mechanisms underlying the synergies of Venetoclax and NB73 using multi-omics and molecular and cellular biology tools in non-t(11;14) myeloma cell lines with high FOXM1 expression. NB73 induces immediate loss of FOXM1, decreases BCL2 expression, and increases Puma expression in myeloma cells. Venetoclax enhances NB73-induced FOXM1 ubiquitination and degradation. The NB73-Venetoclax combination abrogates the binding of FOXM1 to the promoters of genes in the MYC pathway, such as PLK1, MYC, CDC20, and CCNA2, leading to the repression of the transcription of these MYC pathway genes. The PLK1-specific inhibitor GSK461364 synergies with NB73 in suppressing myeloma cell growth. Therefore, NB73 synergizes with Venetoclax in killing myeloma cells. Conclusively, the NB73-Venetoclax combination abolishes FOXM1-mediated transcriptional activation of the MYC pathway, resulting in intensive apoptosis of myeloma cells without t(11;14) but with high FOXM1 expression. Statement of significance This study implicates that targeting FOXM1 will alleviate resistance to BCL2 inhibitor Venetoclax in non-t(11;14) myeloma cells expressing high FOXM1.

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• NB compounds are potent and efficacious FOXM1 inhibitors in high-grade serous ovarian cancer cells

  Journal of Ovarian Research · 2024-05-04 · 10 citations

  articleOpen access

  BACKGROUND: Genetic studies implicate the oncogenic transcription factor Forkhead Box M1 (FOXM1) as a potential therapeutic target in high-grade serous ovarian cancer (HGSOC). We evaluated the activity of different FOXM1 inhibitors in HGSOC cell models. RESULTS: We treated HGSOC and fallopian tube epithelial (FTE) cells with a panel of previously reported FOXM1 inhibitors. Based on drug potency, efficacy, and selectivity, determined through cell viability assays, we focused on two compounds, NB-73 and NB-115 (NB compounds), for further investigation. NB compounds potently and selectively inhibited FOXM1 with lesser effects on other FOX family members. NB compounds decreased FOXM1 expression via targeting the FOXM1 protein by promoting its proteasome-mediated degradation, and effectively suppressed FOXM1 gene targets at both the protein and mRNA level. At the cellular level, NB compounds promoted apoptotic cell death. Importantly, while inhibition of apoptosis using a pan-caspase inhibitor rescued HGSOC cells from NB compound-induced cell death, it did not rescue FOXM1 protein degradation, supporting that FOXM1 protein loss from NB compound treatment is specific and not a general consequence of cytotoxicity. Drug washout studies indicated that FOXM1 reduction was retained for at least 72 h post-treatment, suggesting that NB compounds exhibit long-lasting effects in HGSOC cells. NB compounds effectively suppressed both two-dimensional and three-dimensional HGSOC cell colony formation at sub-micromolar concentrations. Finally, NB compounds exhibited synergistic activity with carboplatin in HGSOC cells. CONCLUSIONS: NB compounds are potent, selective, and efficacious inhibitors of FOXM1 in HGSOC cells and are worthy of further investigation as HGSOC therapeutics.

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Recent grants

• NIH Grant R01CA060514

  NIH · $2.5M · 2004

• NIH Grant R37CA018119

  NIH · $1.9M · 1999

• NIH Grant R01CA018119

  NIH · $4.0M · 2010

• NIH Grant R01HD021524

  NIH · $338k · 1989

• NIH Grant U54HD055787

  NIH · $13.4M · 2014

Frequent coauthors

• John A. Katzenellenbogen

  University of Illinois Urbana-Champaign

  353 shared

• Kathryn E. Carlson

  University of Illinois Urbana-Champaign

  116 shared

• Geoffrey L. Greene

  University of Chicago

  94 shared

• Zeynep Madak‐Erdogan

  71 shared

• K.W. Nettles

  Scripps Research Institute

  63 shared

• Yvonne Ziegler

  University of Illinois Urbana-Champaign

  62 shared

• Sung Hoon Kim

  University of Illinois Urbana-Champaign

  57 shared

• Shubin Sheng

  55 shared

Education

• Postdoctoral Research Scientist, Physiology and Biophysics

  University of Illinois Urbana-Champaign

  1971

• PhD, Biology

  Harvard University

  1970

Awards & honors

• Ernst Oppenheimer Memorial Award of The Endocrine Society fo…
• Thomas A. Murphy University Scholar (1987-1990)
• MERIT Award from National Institutes of Health, National Can…
• Faculty Member of the Year Award, University of Illinois Col…
• American Academy of Arts and Sciences, elected Fellow (1993)