scholarly journals Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Muriel Lainé ◽  
Sean W. Fanning ◽  
Ya-Fang Chang ◽  
Bradley Green ◽  
Marianne E. Greene ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Tumor Growth ◽  
Ligand Binding ◽  
Endocrine Therapy ◽  
Breast Cancers ◽  
Primary Tumor Growth ◽  
Wild Type ◽  
Tumor Growth And Metastasis ◽  
Anti Tumor Activity

Abstract Background Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. Methods Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. Results As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. Conclusions We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

Estrogen Receptor Status by Immunohistochemistry Is Superior to the Ligand-Binding Assay for Predicting Response to Adjuvant Endocrine Therapy in Breast Cancer

1999 ◽  
Vol 17 (5) ◽  
pp. 1474-1474 ◽  
Author(s):  
Jennet M. Harvey ◽  
Gary M. Clark ◽  
C. Kent Osborne ◽  
D. Craig Allred
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Clinical Outcome ◽  
Ligand Binding ◽  
Endocrine Therapy ◽  
Binding Assay ◽  
Adjuvant Endocrine Therapy ◽  
Ligand Binding Assay ◽  
Breast Cancers ◽  
Er Status

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome—especially response to adjuvant endocrine therapy—in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

scholarly journals IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

2020 ◽  
Author(s):  
Sadiya Parveen ◽  
Sumit Siddharth ◽  
Laurene S Cheung ◽  
Alok Kumar ◽  
John R Murphy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Immune Cells ◽  
Diphtheria Toxin ◽  
Triple Negative ◽  
Protein Toxin ◽  
Tumor Growth And Metastasis ◽  
Anti Tumor Activity

ABSTRACTIn many solid tumors including triple-negative breast cancer (TNBC), IL-4 receptor (IL-4R) upregulation has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential and a Th2 response in the tumor microenvironment (TME). Immunosuppressive cells in the TME including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) also express the IL4-R. We hypothesized that selective depletion of IL4-R bearing cells in TNBC may have dual cytotoxic and immunotherapeutic benefit. To selectively target IL-4R+ cells, we genetically constructed, expressed and purified DABIL-4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL-4. We found that DABIL-4 has potent and specific cytotoxic activity against TNBC cells in vitro. In murine TNBC models, DABIL-4 significantly reduced tumor growth, splenomegaly and lung metastases, and this was associated with reductions in MDSC, TAM and regulatory T-cells (Tregs) populations with a concomitant increase in the proportion of IFNγ+ CD8 T-cells. The anti-tumor activity of DABIL-4 was absent in IL-4R KO mice directly implicating IL-4R directed killing as the mechanism of anti-tumor activity. Moreover, NanoString analysis of DABIL-4 treated TNBC tumors revealed marked decline in mRNA transcripts that promote tumorigenesis and metastasis. Our findings demonstrate that DABIL-4 is a potent targeted antitumor agent which depletes both IL-4R bearing tumor cells as well as immunosuppressive cell populations in the TME.STATEMENT OF SIGNIFICANCEIn solid tumors like breast cancer, Interleukin-4 receptor (IL-4R) expression in the tumor microenvironment aids tumor growth and metastasis. IL-4R expression upon host immune cells further dampens antitumor immunity. In this study, we have genetically constructed a fusion protein toxin, DABIL-4, composed of the catalytic and translocation domains of diphtheria toxin and murine IL-4. DABIL-4 showed specific cytotoxicity against triple-negative breast cancer (TNBC) cells in vitro. DABIL-4 also markedly inhibited TNBC tumor growth and metastasis in vivo. The primary activity of DABIL-4 was found to be depletion of IL-4R+ immune cells in combination with direct elimination of tumor cells. In conclusion, DABIL-4 targeting of both tumor and immunosuppressive host cells is a versatile and effective treatment strategy for TNBC.

scholarly journals Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader

2015 ◽  
Vol 22 (5) ◽  
pp. 713-724 ◽  
Author(s):  
Suzanne E Wardell ◽  
Erik R Nelson ◽  
Christina A Chao ◽  
Holly M Alley ◽  
Donald P McDonnell
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Tumor Growth ◽  
Endocrine Therapy ◽  
Cancer Metastasis ◽  
Xenograft Tumor ◽  
Metastatic Setting ◽  
Dose Dependent ◽  
The Brain ◽  
Xenograft Tumor Growth

Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains a first-line treatment for estrogen receptor 1 (ESR1) positive breast cancer. However, tumor resistance limits the duration of response. The clinical efficacy of fulvestrant, a selective ER degrader (SERD) that triggers receptor degradation, has confirmed that ESR1 often remains engaged in endocrine therapy resistant cancers. Recently developed, selective ER modulators (SERMs)/SERD hybrids (SSHs) that facilitate ESR1 degradation in breast cancer cells and reproductive tissues have been advanced as an alternative treatment for advanced breast cancer, particularly in the metastatic setting. RAD1901 is one SSH currently being evaluated clinically that is unique among ESR1 modulators in that it readily enters the brain, a common site of breast cancer metastasis. In this study, RAD1901 inhibited estrogen activation of ESR1in vitroandin vivo, inhibited estrogen-dependent breast cancer cell proliferation and xenograft tumor growth, and mediated dose-dependent downregulation of ESR1 protein. However, doses of RAD1901 insufficient to induce ESR1 degradation were shown to result in the activation of ESR1 target genes and in the stimulation of xenograft tumor growth. RAD1901 is an SSH that exhibits complex pharmacology in breast cancer models, having dose-dependent agonist/antagonist activity displayed in a tissue-selective manner. It remains unclear how this unique pharmacology will impact the utility of RAD1901 for breast cancer treatment. However, being the only SERD currently known to access the brain, RAD1901 merits evaluation as a targeted therapy for the treatment of breast cancer brain metastases.

A CXCR4 Antagonist CTCE-9908 Inhibits Primary Tumor Growth and Metastasis of Breast Cancer

2009 ◽  
Vol 155 (2) ◽  
pp. 231-236 ◽  
Author(s):  
Eugene H. Huang ◽  
Balraj Singh ◽  
Massimo Cristofanilli ◽  
Juri Gelovani ◽  
Caimiao Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Primary Tumor Growth ◽  
Cxcr4 Antagonist ◽  
Tumor Growth And Metastasis

scholarly journals Update on the Role of NFκB in Promoting Aggressive Phenotypes of Estrogen Receptor–Positive Breast Cancer

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Author(s):  
Emily Smart ◽  
Svetlana E Semina ◽  
Jonna Frasor
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Signaling Pathway ◽  
Endocrine Resistance ◽  
Dimethyl Fumarate ◽  
Therapy Resistance ◽  
Molecular Characteristics ◽  
Breast Cancers ◽  
Estrogen Receptor Positive

Abstract The majority of breast cancers are diagnosed as estrogen receptor–positive (ER+) and respond well to ER-targeted endocrine therapy. Despite the initial treatability of ER+ breast cancer, this subtype still accounts for the majority of deaths. This is partly due to the changing molecular characteristics of tumors as they progress to aggressive, metastatic, and frequently therapy resistant disease. In these advanced tumors, targeting ER alone is often less effective, as other signaling pathways become active, and ER takes on a redundant or divergent role. One signaling pathway whose crosstalk with ER has been widely studied is the nuclear factor kappa B (NFκB) signaling pathway. NFκB is frequently implicated in ER+ tumor progression to an aggressive disease state. Although ER and NFκB frequently co-repress each other, it has emerged that the 2 pathways can positively converge to play a role in promoting endocrine resistance, metastasis, and disease relapse. This will be reviewed here, paying particular attention to new developments in the field. Ultimately, finding targeted therapies that remain effective as tumors progress remains one of the biggest challenges for the successful treatment of ER+ breast cancer. Although early attempts to therapeutically block NFκB activity frequently resulted in systemic toxicity, there are some effective options. The drugs parthenolide and dimethyl fumarate have both been shown to effectively inhibit NFκB, reducing tumor aggressiveness and reversing endocrine therapy resistance. This highlights the need to revisit targeting NFκB in the clinic to potentially improve outcome for patients with ER+ breast cancer.

scholarly journals The Role of Estrogen in the Development of Breast Cancer

2021 ◽  
Vol 7 (2) ◽  
pp. 231-241
Author(s):  
Nikki Aldi Massardi
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Tumor Growth ◽  
Endocrine Therapy ◽  
Breast Cancers ◽  
Mitogenic Effect ◽  
Human Breast ◽  
Clinically Significant ◽  
Circulating Levels

Breast cancer is a hormone-dependent disease that relies on the mitogenic effect ofestrogen to increase tumorigenesis and tumor growth. Clinically significant levels ofestrogen-α receptor (ERα) expression are seen in 80% of human breast cancers,whereas progesterone receptor is expressed in 55% of human breast cancers. Thesedata are one of the bases for the development of endocrine therapy. Endocrinetherapy is therapy that targets the pathway and synthesis of estrogen, by blocking itvia receptors, reducing circulating levels of estrogen, or suppressing estrogensynthesis in the tissues of women diagnosed with breast cancer.

scholarly journals Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

2016 ◽  
Author(s):  
Jeffrey F. Hiken ◽  
James I. McDonald ◽  
Keith F. Decker ◽  
Cesar Sanchez ◽  
Jeremy Hoog ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Cancer Recurrence ◽  
Therapy Resistance ◽  
Epigenetic Mechanism ◽  
Prostaglandin E ◽  
Breast Cancers ◽  
Estrogen Production

AbstractApproximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance—especially epigenetic events that alter gene expression—are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment.

scholarly journals Nef-M1, a CXCR4 Peptide Antagonist, Enhances Apoptosis and Inhibits Primary Tumor Growth and Metastasis in Breast Cancer

2013 ◽  
Vol 04 (04) ◽  
pp. 898-906 ◽  
Author(s):  
Harvey Bumpers ◽  
Ming-Bo Huang ◽  
Venkat Katkoori ◽  
Upender Manne ◽  
Vincent Bond
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Primary Tumor Growth ◽  
Peptide Antagonist ◽  
Tumor Growth And Metastasis

scholarly journals Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Esmael Besufikad Belachew ◽  
Dareskedar Tsehay Sewasew
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Endocrine Resistance ◽  
Therapeutic Modality ◽  
Breast Cancers ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

The estrogen receptor is a vital receptor for therapeutic targets in estrogen receptor-positive breast cancer. The main strategy for the treatment of estrogen receptor-positive breast cancers is blocking the estrogen action on estrogen receptors by endocrine therapy but this can be restricted via endocrine resistance. Endocrine resistance occurs due to both de novo and acquired resistance. This review focuses on the mechanisms of the ligand-dependent and ligand-independent pathways and other coregulators, which are responsible for endocrine resistance. It concludes that combinatorial drugs that target different signaling pathways and coregulatory proteins together with endocrine therapy could be a novel therapeutic modality to stop endocrine resistance.

Sign in / Sign up

Export Citation Format

Share Document