Racial differences in endometrial cancer genomics and outcomes using UNCseq targeted DNA sequencing.

Objective: To use an institution-sponsored targeted sequencing effort to characterize the genomic differences in endometrioid and serous endometrial cancers (ECs) between Black and White patients and to investigate the impact on clinical outcomes.

Methods: Tumor tissue from Black and White patients with serous or endometrioid ECs underwent DNA sequencing using the UNCseq panel. Progression-free survival (PFS) and overall survival (OS) were assessed for all patients and within histologic and molecular subcategories using clinicopathologic data from the medical record.

Transcriptomic Predictors of Survival for Palbociclib + Endocrine Therapy Versus Capecitabine in Aromatase Inhibitor-Resistant Breast Cancer From the GEICAM/2013-02 PEARL Trial.

Purpose: For hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC), first-line cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) is the standard of care. They are also used after progression on first-line aromatase inhibitors (AIs), but some patients may respond better to chemotherapy-based options. We examined tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET versus capecitabine in AI-resistant HR+/HER2- MBC.

Prognostic and molecular multi-platform analysis of CALGB 40603 (Alliance) and public triple-negative breast cancer datasets.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease that remains challenging to target with traditional therapies and to predict risk. We provide a comprehensive characterization of 238 stage II-III TNBC tumors with paired RNA and DNA sequencing data from the CALGB 40603 (Alliance) clinical trial, along with 448 stage II-III TNBC tumors with paired RNA and DNA data from three additional datasets. We identify DNA mutations associated with RNA-based subtypes, specific TP53 missense mutations compatible with potential neoantigen activity, and a consistently highly altered copy number landscape.

A randomized phase II/III study of paclitaxel/carboplatin/metformin versus paclitaxel/carboplatin/placebo as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: An NRG oncology/GOG study.

Introduction: We evaluated the efficacy of the addition of the anti-diabetic drug metformin to standard-of-care paclitaxel and carboplatin (PC) in patients with advanced and recurrent endometrial cancer (EC).

Methods: In this phase II/III trial, EC patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) disease were randomly assigned to PC/metformin (850 mg BID) versus PC/placebo. Metformin or placebo was continued as maintenance therapy after completion of PC until disease progression.

Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy.

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection.

Transcriptomic changes underlying EGFR inhibitor resistance in human and mouse models of basal-like breast cancer.

The goals of this study were to identify transcriptomic changes that arise in basal-like breast cancer cells during the development of resistance to epidermal growth factor receptor inhibitors (EGFRi) and to identify drugs that are cytotoxic once EGFRi resistance occurs. Human patient-derived xenografts (PDXs) were grown in immunodeficient mice and treated with a set of EGFRi; the EGFRi erlotinib was selected for more expansive in vivo studies. Single-cell RNA sequencing was performed on mammary tumors from the basal-like PDX WHIM2 that was treated with vehicle or erlotinib for 9 weeks.

Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells.

Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice.

The MMTV-Wnt1 murine model produces two phenotypically distinct subtypes of mammary tumors with unique therapeutic responses to an EGFR inhibitor.

The Wnt gene family encodes an evolutionarily conserved group of proteins that regulate cell growth, differentiation and stem cell self-renewal. Aberrant Wnt signaling in human breast tumors has been proposed as a driver of tumorigenesis, especially in the basal-like tumor subtype where canonical Wnt signaling is both enriched and predictive of poor clinical outcomes. The development of effective Wnt-based therapeutics, however, has been slowed in part by a limited understanding of the context-dependent nature with which these aberrations influence breast tumorigenesis.

A mouse model featuring tissue-specific deletion of p53 and Brca1 gives rise to mammary tumors with genomic and transcriptomic similarities to human basal-like breast cancer.

Purpose And Methods: In human basal-like breast cancer, mutations and deletions in TP53 and BRCA1 are frequent oncogenic events. Thus, we interbred mice expressing the CRE-recombinase with mice harboring loxP sites at TP53 and BRCA1 (K14-Cre; p53 Brca1) to test the hypothesis that tissue-specific deletion of TP53 and BRCA1 would give rise to tumors reflective of human basal-like breast cancer.

Results: In support of our hypothesis, these transgenic mice developed tumors that express basal-like cytokeratins and demonstrated intrinsic gene expression features similar to human basal-like tumors.

Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers.

Targeted therapies against basal-like breast tumors, which are typically 'triple-negative breast cancers (TNBCs)', remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model.

Overview of Genetically Engineered Mouse Models of Distinct Breast Cancer Subtypes.

Advances in the screening of new therapeutic options have significantly reduced the breast cancer death rate over the last decade. Despite these advances, breast cancer remains the second leading cause of cancer death among women. This is due in part to the complexity of the disease, which is characterized by multiple subtypes that are driven by different genetic mechanisms and that likely arise from different cell types of origin.

c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression.

Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments.

Luminal progenitor and fetal mammary stem cell expression features predict breast tumor response to neoadjuvant chemotherapy.

Mammary gland morphology and physiology are supported by an underlying cellular differentiation hierarchy. Molecular features associated with particular cell types along this hierarchy may contribute to the biological and clinical heterogeneity observed in human breast carcinomas. Investigating the normal cellular developmental phenotypes in breast tumors may provide new prognostic paradigms, identify new targetable pathways, and explain breast cancer subtype etiology.

Transcriptomic classification of genetically engineered mouse models of breast cancer identifies human subtype counterparts.

Background: Human breast cancer is a heterogeneous disease consisting of multiple molecular subtypes. Genetically engineered mouse models are a useful resource for studying mammary cancers in vivo under genetically controlled and immune competent conditions. Identifying murine models with conserved human tumor features will facilitate etiology determinations, highlight the effects of mutations on pathway activation, and should improve preclinical drug testing.

Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis.

The vasculature serves as the main conduit for breast tumor metastases and is a target of therapeutics in many tumor types. In this study, we aimed to determine if tumor-associated vascular properties could help to explain the differences observed in metastagenicity across the intrinsic subtypes of human breast tumors. Analysis of gene expression signatures from more than 3,000 human breast tumors found that genomic programs that measured vascular quantity, vascular proliferation, and a VEGF/Hypoxia-signature were the most highly expressed in claudin-low and basal-like tumors.

Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.

Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer.

Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling.

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs.

Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models.

Purpose: Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to in vitro and xenograft systems.

Experimental Design: We assessed the activity of 16 treatment regimens in a RAS-driven, Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B (MMTV-Neu GEMM).

Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast cancer driver.

Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity. Relevant mouse models are powerful for untangling this problem because such heterogeneity can be controlled. Inbred Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors that have tumor gene expression profiles closely resembling mature human mammary luminal cell signatures.

LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma.

Germline mutations in LKB1 (STK11) are associated with the Peutz-Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (±p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC family kinase (SFK) YES, increased expression of WNT target genes, and expansion of a CD24(+) cell population, which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24(-) cells.

Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation.

The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly misregulated signaling pathways in human cancers, but its impact on the tumor microenvironment has not been considered as deeply as its autonomous impact on tumor cells. In this study, we show that NF-κB is activated by the two most common PI3K mutations, PIK3CA E545K and H1047R. We found that markers of NF-κB are most strongly upregulated under conditions of growth factor deprivation.

A potential role for glucose transporters in the evolution of human brain size.

Differences in cognitive abilities and the relatively large brain are among the most striking differences between humans and their closest primate relatives. The energy trade-off hypothesis predicts that a major shift in energy allocation among tissues occurred during human origins in order to support the remarkable expansion of a metabolically expensive brain. However, the molecular basis of this adaptive scenario is unknown.

Comparative expression analysis of the phosphocreatine circuit in extant primates: Implications for human brain evolution.

While the hominid fossil record clearly shows that brain size has rapidly expanded over the last ~2.5 M.yr.

A pipeline to determine RT-QPCR control genes for evolutionary studies: application to primate gene expression across multiple tissues.

Because many species-specific phenotypic differences are assumed to be caused by differential regulation of gene expression, many recent investigations have focused on measuring transcript abundance. Despite the availability of high-throughput platforms, quantitative real-time polymerase chain reaction (RT-QPCR) is often the method of choice because of its low cost and wider dynamic range. However, the accuracy of this technique heavily relies on the use of multiple valid control genes for normalization.

Both noncoding and protein-coding RNAs contribute to gene expression evolution in the primate brain.

Despite striking differences in cognition and behavior between humans and our closest primate relatives, several studies have found little evidence for adaptive change in protein-coding regions of genes expressed primarily in the brain. Instead, changes in gene expression may underlie many cognitive and behavioral differences. Here, we used digital gene expression: tag profiling (here called Tag-Seq, also called DGE:tag profiling) to assess changes in global transcript abundance in the frontal cortex of the brains of 3 humans, 3 chimpanzees, and 3 rhesus macaques.