Metabolic Switch in Endocrine Resistant Estrogen Receptor Positive Breast Cancer.

Purpose: The development of endocrine resistance remains a significant challenge in the clinical management of estrogen receptor-positive () breast cancer. Metabolic reprogramming is a prominent component of endocrine resistance and a potential therapeutic intervention point. However, a limited understanding of which metabolic changes are conserved across the heterogeneous landscape of ER+ breast cancer or how metabolic changes factor into ER DNA binding patterns hinder our ability to target metabolic adaptation as a treatment strategy.

Maf1 Cooperates with Progesterone Receptor to Repress RNA Polymerase III Transcription of Select tRNAs.

Progesterone receptors (PR) can regulate transcription by RNA Polymerase III (Pol III), which transcribes small non-coding RNAs, including all transfer RNAs (tRNAs). We have previously demonstrated that PR is associated with the Pol III complex at tRNA genes and that progestins downregulate tRNA transcripts in breast tumor models. To further elucidate the mechanism of PR-mediated regulation of Pol III, we studied the interplay between PR, the Pol III repressor Maf1, and TFIIIB, a core transcription component.

Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells.

Background: Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER+ breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor.

Methods: ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived.

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.

The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands.

Pertuzumab as second‑ or later‑line therapy for human epidermal growth factor receptor 2‑positive metastatic breast cancer: A clinical experience.

Trastuzumab and pertuzumab with taxane-based chemotherapy are considered the first-line standard therapy for human epidermal growth factor receptor 2 ()-positive metastatic breast cancer (mBC). Pertuzumab is also a later-line therapy for mBC in Switzerland, although limited safety and efficacy data are available. The present study assessed the therapeutic regimens, toxicities and clinical outcomes after second- or later-line pertuzumab therapy in patients with mBC who did not receive pertuzumab as a first-line therapy.

Identification of a novel ER-NFĸB-driven stem-like cell population associated with relapse of ER+ breast tumors.

Background: Up to 40% of patients with estrogen receptor-positive (ER+) breast cancer experience relapse. This can be attributed to breast cancer stem cells (BCSCs), which are known to be involved in therapy resistance, relapse, and metastasis. Therefore, there is an urgent need to identify genes/pathways that drive stem-like cell properties in ER+ breast tumors.

Transcription factor-nucleosome dynamics from plasma cfDNA identifies ER-driven states in breast cancer.

Genome-wide binding profiles of estrogen receptor (ER) and FOXA1 reflect cancer state in ER breast cancer. However, routine profiling of tumor transcription factor (TF) binding is impractical in the clinic. Here, we show that plasma cell-free DNA (cfDNA) contains high-resolution ER and FOXA1 tumor binding profiles for breast cancer.

Cytokeratins 5 and 17 Maintain an Aggressive Epithelial State in Basal-Like Breast Cancer.

Unlabelled: Basal-like breast cancers (BLBC) are the most common triple-negative subtype (hormone receptor and HER2 negative) with poor short-term disease outcome and are commonly identified by expression of basal cytokeratins (CK) 5 and 17. The goal of this study was to investigate whether CK5 and CK17 play a role in adverse behavior of BLBC cells. BLBC cell lines contain heterogeneous populations of cells expressing CK5, CK17, and the mesenchymal filament protein vimentin.

ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation.

Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes.

Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.

Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS).

Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1.

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth.

Advances in Analyzing the Breast Cancer Lipidome and Its Relevance to Disease Progression and Treatment.

Abnormal lipid metabolism is common in breast cancer with the three main subtypes, hormone receptor (HR) positive, human epidermal growth factor 2 (HER2) positive, and triple negative, showing common and distinct lipid dependencies. A growing body of studies identify altered lipid metabolism as impacting breast cancer cell growth and survival, plasticity, drug resistance, and metastasis. Lipids are a class of nonpolar or polar (amphipathic) biomolecules that can be produced in cells via de novo synthesis or acquired from the microenvironment.

Neoadjuvant endocrine therapy expands stromal populations that predict poor prognosis in estrogen receptor-positive breast cancer.

The tumor microenvironment (TME) is an important modulator of response and resistance to endocrine therapy in estrogen receptor alpha (ER) positive breast cancer. Endocrine therapy is highly effective at reducing tumor burden and preventing recurrence in most estrogen receptor alpha (ER) positive breast cancers. Existing drugs work either directly by targeting tumor-cell ER or indirectly by inhibiting estrogen production in stromal cells with aromatase inhibitors (AI).

The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer.

The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies. Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses.

Enhanced Antitumor Immunity via Endocrine Therapy Prevents Mammary Tumor Relapse and Increases Immune Checkpoint Blockade Sensitivity.

The role of active antitumor immunity in hormone receptor-positive (HR) breast cancer has been historically underlooked. The aim of this study was to determine the contribution of the immune system to antiprogestin-induced tumor growth inhibition using a hormone-dependent breast cancer model. BALB/c-GFP bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFP (NSG-R) mouse model.

Exogenous Thyroid Hormone Is Associated with Shortened Survival and Upregulation of High-Risk Gene Expression Profiles in Steroid Receptor-Positive Breast Cancers.

Purpose: Thyroid disease is a frequent comorbidity in women with breast cancer, and many require thyroid hormone replacement therapy (THRT). We postulated that THRT has a deleterious clinical effect mechanistically through hormonal interactions, nuclear receptor cross-talk, and upregulation of high-risk breast cancer genes.

Experimental Design: Observational studies of patients with lymph node-negative (LN) breast cancer ( = 820 and = 160) were performed to test interactions between THRT and clinical, histologic, outcome, and treatment variables.

Analysis of circulating breast cancer cell heterogeneity and interactions with peripheral blood mononuclear cells.

For solid tumors, extravasation of cancer cells and their survival in circulation represents a critical stage of the metastatic process that lacks complete understanding. Gaining insight into interactions between circulating tumor cells (CTCs) and other peripheral blood mononuclear cells (PBMCs) may provide valuable prognostic information. The purpose of this study was to use single-cell RNA-sequencing (scRNA-seq) of liquid biopsies from breast cancer patients to begin defining intravascular interactions.

New generation breast cancer cell lines developed from patient-derived xenografts.

Background: Breast cancer is a highly heterogeneous disease characterized by multiple histologic and molecular subtypes. While a myriad of breast cancer cell lines have been developed over the past 60 years, estrogen receptor alpha (ER)+ disease and some mutations associated with this subtype remain underrepresented. Here we describe six breast cancer cell lines derived from patient-derived xenografts (PDX) and their general characteristics.

90 YEARS OF PROGESTERONE: Progesterone and progesterone receptors in breast cancer: past, present, future.

Progesterone and progesterone receptors (PR) have a storied albeit controversial history in breast cancers. As endocrine therapies for breast cancer progressed through the twentieth century from oophorectomy to antiestrogens, it was recognized in the 1970s that the presence of estrogen receptors (ER) alone could not efficiently predict treatment responses. PR, an estrogen regulated protein, became the first prognostic and predictive marker of response to endocrine therapies.

Fibroblast subtypes define a metastatic matrisome in breast cancer.

Small primary breast cancers can show surprisingly high potential for metastasis. Clinical decision-making for tumor aggressiveness, including molecular profiling, relies primarily on analysis of the cancer cells. Here we show that this analysis is insufficient - that the stromal microenvironment of the primary tumor plays a key role in tumor cell dissemination and implantation at distant sites.

Cytokeratin 5 alters β-catenin dynamics in breast cancer cells.

Estrogen receptor (ER) positive breast cancers often contain subpopulations of cells that express the intermediate filament protein cytokeratin 5 (CK5). CK5+ cells are enriched in cancer stem cell (CSC) properties, can be induced by progestins, and predict poor prognosis in ER+ breast cancer. We established through CK5 knockout and overexpression in ER+ breast cancer cell lines that CK5 is important for tumorsphere formation, prompting us to speculate that CK5 has regulatory activity in CSCs.