CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.

The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation.

Preclinical Mouse Intraductal Model (MIND) to Study Metastatic Dormancy in Estrogen Receptor-Positive Breast Cancer.

Here, we describe a clinically relevant xenograft model of hormone receptor-positive breast cancer that maintains estrogen receptor (ER) status without the need for exogenous supplementation of hormones. The naturally low 17-β-estradiol levels in host mice recapitulate levels seen in post-menopausal women. By introducing breast cancer cells directly into their "natural" microenvironment of the milk ducts, these cells maintain hormone receptor status, model the clinical progression of the disease, and develop ER metastatic lesions or dormant micrometastatic lesions in the case of ER BC.

EMBER creates a unified space for independent breast cancer transcriptomic datasets enabling precision oncology.

Transcriptomics has revolutionized biomedical research and refined breast cancer subtyping and diagnostics. However, wider use in clinical practice is hampered for a number of reasons including the application of transcriptomic signatures as single sample predictors. Here, we present an embedding approach called EMBER that creates a unified space of 11,000 breast cancer transcriptomes and predicts phenotypes of transcriptomic profiles on a single sample basis.

Rapid autopsies to enhance metastatic research: the UPTIDER post-mortem tissue donation program.

Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples.

Metabolic dependencies of metastasis-initiating cells in female breast cancer.

Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage.

Tumor dormancy: EMT beyond invasion and metastasis.

More than two-thirds of cancer-related deaths are attributable to metastases. In some tumor types metastasis can occur up to 20 years after diagnosis and successful treatment of the primary tumor, a phenomenon termed late recurrence. Metastases arise from disseminated tumor cells (DTCs) that leave the primary tumor early on in tumor development, either as single cells or clusters, adapt to new environments, and reduce or shut down their proliferation entering a state of dormancy for prolonged periods of time.

Optimized Modeling of Metastatic Triple-Negative Invasive Lobular Breast Carcinoma.

Invasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease.

IFNγ-induced stem-like state of cancer cells as a driver of metastatic progression following immunotherapy.

Despite the remarkable success of immune checkpoint blockade (ICB) therapy, most cancer patients still do not respond. We now find that immunotherapy can induce stem-like properties in tumors. Using mouse models of breast cancer, we observe that cancer stem cells (CSCs) show not only enhanced resistance to T cell cytotoxicity, but that interferon gamma (IFNγ) produced by activated T cells directly converts non-CSCs to CSCs.

TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management.

Targeting the Progesterone Receptor in Breast Cancer: Mind the Short Form!

The presurgical window of opportunity trial (WOT) MIPRA provides evidence that neoadjuvant treatment with the progesterone receptor (PR) antagonist mifepristone (RU486) may benefit patients with estrogen receptor-positive (ER+) breast cancer characterized by a high ratio of PR-A versus PR-B isoform (>1.5), suggesting that PR may be targeted in a subset of patients. See related article by Elía et al.

Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence.

More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER). A clinical challenge of ER BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models.

RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer.

Multigene assays for molecular subtypes and biomarkers can aid management of early invasive breast cancer. Using RNA-sequencing we aimed to develop single-sample predictor (SSP) models for clinical markers, subtypes, and risk of recurrence (ROR). A cohort of 7743 patients was divided into training and test set.

Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions.

Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancer (BC) cases and responds well to endocrine treatment when estrogen receptor α-positive (ER) yet differs in many biological aspects from other ER BC subtypes. Up to 30% of patients with ILC will develop late-onset metastatic disease up to ten years after initial tumor diagnosis and may experience failure of systemic therapy. Unfortunately, preclinical models to study ILC progression and predict the efficacy of novel therapeutics are scarce.

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1.

Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E-cadherin. It has clinical features distinct from other estrogen receptor-positive (ER ) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC-derived breast cancer cell lines, SUM-44 PE and MDA-MB-134-VI cells, into the mouse milk ducts.

IL6/STAT3 Signaling Hijacks Estrogen Receptor α Enhancers to Drive Breast Cancer Metastasis.

The cytokine interleukin-6 (IL6) and its downstream effector STAT3 constitute a key oncogenic pathway, which has been thought to be functionally connected to estrogen receptor α (ER) in breast cancer. We demonstrate that IL6/STAT3 signaling drives metastasis in ER breast cancer independent of ER. STAT3 hijacks a subset of ER enhancers to drive a distinct transcriptional program.

Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity.

Functional studies giving insight into the biology of circulating tumor cells (CTCs) remain scarce due to the low frequency of CTCs and lack of appropriate models. Here, we describe the characterization of a novel CTC-derived breast cancer cell line, designated CTC-ITB-01, established from a patient with metastatic estrogen receptor-positive (ER ) breast cancer, resistant to endocrine therapy. CTC-ITB-01 remained ER in culture, and copy number alteration (CNA) profiling showed high concordance between CTC-ITB-01 and CTCs originally present in the patient with cancer at the time point of blood draw.

90 YEARS OF PROGESTERONE: Progesterone receptor signaling in the normal breast and its implications for cancer.

Progesterone is considered as the pregnancy hormone and acts on many different target tissues. Progesterone receptor (PR) signaling is important for normal development and the physiologic function of the breast and impinges on breast carcinogenesis. Both systemically and locally, in the breast epithelium, there are multiple layers of complexity to progesterone action, many of which have been revealed through experiments in mice.

Sequential Bone-Marrow Cell Delivery of VEGFA/S1P Improves Vascularization and Limits Adverse Cardiac Remodeling After Myocardial Infarction in Mice.

Microvascular dysfunction and resulting tissue hypoxia is a major contributor to the pathogenesis and evolution of cardiovascular diseases (CVD). Diverse gene and cell therapies have been proposed to preserve the microvasculature or boost angiogenesis in CVD, with moderate benefit. This study tested the impact of sequential delivery by bone-marrow (BM) cells of the pro-angiogenic factors vascular endothelial growth factor (VEGFA) and sphingosine-1-phosphate (S1P) in a myocardial infarction model.

Short-lived AUF1 p42-binding mRNAs of RANKL and BCL6 have two distinct instability elements each.

Regulation of mRNA stability by RNA-protein interactions contributes significantly to quantitative aspects of gene expression. We have identified potential mRNA targets of the AU-rich element binding protein AUF1. Myc-tagged AUF1 p42 was induced in mouse NIH/3T3 cells and RNA-protein complexes isolated using anti-myc tag antibody beads.

The challenges of modeling hormone receptor-positive breast cancer in mice.

Estrogen receptor-positive (ER+) tumors account for 70-80% of all breast cancer (BC) cases and are characterized by estrogen dependency for their growth. Endocrine therapies using estrogen receptor antagonists or aromatase inhibitors represent a key component of the standard of care for these tumors. The occurrence of de novo or acquired resistance to estrogen withdrawal represents an important clinical problem, impacting on patient survival.

A Subset of Cancer-Associated Fibroblasts Determines Therapy Resistance.

While functional heterogeneity of fibroblastic cells populating the tumor microenvironment is increasingly recognized, lack of definitive markers complicates elucidation of roles among ostensibly distinctive fibroblastic states. In this issue of Cell, Su et al. characterize a new pro-tumorigenic cancer-associated fibroblast subset mediating chemoresistance defined and driven by a novel signaling pathway.

Cross-Tissue Identification of Somatic Stem and Progenitor Cells Using a Single-Cell RNA-Sequencing Derived Gene Signature.

A long-standing question in biology is whether multipotent somatic stem and progenitor cells (SSPCs) feature molecular properties that could guide their system-independent identification. Population-based transcriptomic studies have so far not been able to provide a definite answer, given the rarity and heterogeneous nature of these cells. Here, we exploited the resolving power of single-cell RNA-sequencing to develop a computational model that is able to accurately distinguish SSPCs from differentiated cells across tissues.

Long-Term Engraftment of Primary Bone Marrow Stromal Cells Repairs Niche Damage and Improves Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell (HSC) transplantation represents a curative treatment for various hematological disorders. However, delayed reconstitution of innate and adaptive immunity often causes fatal complications. HSC maintenance and lineage differentiation are supported by stromal niches, and we now find that bone marrow stroma cells (BMSCs) are severely and permanently damaged by the pre-conditioning irradiation required for efficient HSC transplantation.

Patient-derived xenograft (PDX) models in basic and translational breast cancer research.

Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational preclinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and "Triple-negative" (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics.

Contractility Assay for Established Myoepithelial Cell Lines.

The capacity of mammary myoepithelial cells to contract in response to suckling stimuli is essential for lactation. We describe here a protocol for studying the contractile activity of myoepithelial cells in vitro. This protocol includes the establishment of stable myoepithelial cell lines from mouse mammary glands and quantitative evaluation of the contraction and subsequent relaxation of cultured myoepithelial cells in response to oxytocin.