Spatial Proteomics of the Normal Breast Collagen Stroma: Links to BI-RADS Categories and Body Mass Index.

Collagen breast stroma is the basis of increased breast density and a well-established breast cancer risk factor, yet proteomic regulation of normal breast stroma remains poorly defined. This study reports spatial regulation of the collagen proteome in normal breast tissue sections annotated by clinical characteristics. Normal breast samples from the Susan G.

Ancestry-linked stromal variations impact breast epithelial cell invasion.

Breast cancer disproportionately affects women of African ancestry (AA) in part due to biological factors that affect disease outcome. A cell population that expresses PROCR, ZEB1, and PDGFRα (PZP) was recently found to be enriched in breast stroma from healthy AA donors, but only in tumor-adjacent tissues from donors of European ancestry (EA). Here, we show that PZP cells conferred invasive capacity to epithelial cells of both AA and EA origin in 3D cell models wherein cells exhibited leader-follower behaviors during extracellular matrix invasion.

MammOnc-DB, an integrative breast cancer data analysis platform for target discovery.

Breast cancer (BCa), a leading malignancy among women, is characterized by morphological and molecular heterogeneity. While early-stage, hormone receptor, and HER2-positive BCa are treatable, triple-negative BCa and metastatic BCa remains largely untreatable. Advances in sequencing and proteomic technologies have improved our understanding of the molecular alterations that occur during BCa initiation and progression and enabled identification of subclass-specific biomarkers and therapeutic targets.

Spatial localization of collagen hydroxylated proline site variation as an ancestral trait in the breast cancer microenvironment.

Collagen stroma interactions within the extracellular microenvironment of breast tissue play a significant role in breast cancer, including risk, progression, and outcomes. Hydroxylation of proline (HYP) is a common post-translational modification directly linked to breast cancer survival and progression. Changes in HYP status lead to alterations in epithelial cell signaling, extracellular matrix remodeling, and immune cell recruitment.

Ancestry-linked stromal variations impact breast epithelial cell invasion.

Breast cancer is a significant health challenge worldwide, and disproportionately affects women of African ancestry (AA) who experience higher mortality rates relative to other racial/ethnic groups. Several studies have pointed to biological factors that affect breast cancer outcomes. A recently discovered stromal cell population that expresses P ROCR, Z EB1 and P DGFRα (PZP cells) was found to be enriched in normal healthy breast tissue from AA donors, and only in tumor adjacent tissues from donors of European ancestry (EA).

MammOnc-DB, an integrative breast cancer data analysis platform for target discovery.

Breast cancer (BCa) is one of the most common malignancies among women worldwide. It is a complex disease that is characterized by morphological and molecular heterogeneity. In the early stages of the disease, most BCa cases are treatable, particularly hormone receptor-positive and HER2-positive tumors.

A triple hormone receptor ER, AR, and VDR signature is a robust prognosis predictor in breast cancer.

Background: Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures.

Methods: We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers.

Single-nucleus chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry.

Single-nucleus analysis allows robust cell-type classification and helps to establish relationships between chromatin accessibility and cell-type-specific gene expression. Here, using samples from 92 women of several genetic ancestries, we developed a comprehensive chromatin accessibility and gene expression atlas of the breast tissue. Integrated analysis revealed ten distinct cell types, including three major epithelial subtypes (luminal hormone sensing, luminal adaptive secretory precursor (LASP) and basal-myoepithelial), two endothelial and adipocyte subtypes, fibroblasts, T cells, and macrophages.

Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies.

Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air.

Spatial N-glycomics of the normal breast microenvironment reveals fucosylated and high-mannose N-glycan signatures related to BI-RADS density and ancestry.

Higher breast cancer mortality rates continue to disproportionally affect black women (BW) compared to white women (WW). This disparity is largely due to differences in tumor aggressiveness that can be related to distinct ancestry-associated breast tumor microenvironments (TMEs). Yet, characterization of the normal microenvironment (NME) in breast tissue and how they associate with breast cancer risk factors remains unknown.

Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis.

The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic.

Mutant RAS-driven Secretome Causes Skeletal Muscle Defects in Breast Cancer.

Unlabelled: Cancer-induced skeletal muscle defects differ in severity between individuals with the same cancer type. Cancer subtype-specific genomic aberrations are suggested to mediate these differences, but experimental validation studies are very limited. We utilized three different breast cancer patient-derived xenograft (PDX) models to correlate cancer subtype with skeletal muscle defects.

Identification and Characterization of a Small Molecule Bcl-2 Functional Converter.

Unlabelled: Cancer cells exploit the expression of anti-apoptotic protein Bcl-2 to evade apoptosis and develop resistance to therapeutics. High levels of Bcl-2 leads to sequestration of pro-apoptotic proteins causing the apoptotic machinery to halt. In this study, we report discovery of a small molecule, BFC1108 (5-chloro-N-(2-ethoxyphenyl)-2-[(4-methoxybenzyol)amino]benzamide), which targets Bcl-2 and converts it into a pro-apoptotic protein.

Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene.

Unlabelled: Single-cell transcriptomics studies have begun to identify breast epithelial cell and stromal cell specific transcriptome differences between BRCA1/2 mutation carriers and non-carriers. We generated a single-cell transcriptome atlas of breast tissues from BRCA1, BRCA2 mutation carriers and compared this single-cell atlas of mutation carriers with our previously described single-cell breast atlas of healthy non-carriers. We observed that BRCA1 but not BRCA2 mutations altered the ratio between basal (basal-myoepithelial), luminal progenitor (luminal adaptive secretory precursor, LASP), and mature luminal (luminal hormone sensing) cells in breast tissues.

Stromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent.

The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to ductal epithelial cells in normal breasts of women of African ancestry compared to those of European ancestry. In this study, we demonstrate that these cells have properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRα and transdifferentiate into adipogenic and osteogenic lineages.

A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle.

Skeletal muscle dysfunction or reprogramming due to the effects of the cancer secretome is observed in multiple malignancies. Although mouse models are routinely used to study skeletal muscle defects in cancer, because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required. Here, we establish simplified multiple skeletal muscle stem cell lines (hMuSCs), which can be differentiated into myotubes.

TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer.

Unlabelled: Study of genomic aberrations leading to immortalization of epithelial cells has been technically challenging due to the lack of isogenic models. To address this, we used healthy primary breast luminal epithelial cells of different genetic ancestry and their hTERT-immortalized counterparts to identify transcriptomic changes associated with immortalization. Elevated expression of TONSL (Tonsoku-like, DNA repair protein) was identified as one of the earliest events during immortalization.

Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue.

Market drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Protein arginine methyltransferase 5 (PRMT5) overexpression has been linked to promoting the tumor phenotype in several cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC), making PRMT5 an important target for cancer therapy.

Therapeutic Activity of the Lansoprazole Metabolite 5-Hydroxy Lansoprazole Sulfide in Triple-Negative Breast Cancer by Inhibiting the Enoyl Reductase of Fatty Acid Synthase.

Fatty acid synthase (FASN), a sole cytosolic enzyme responsible for de-novo lipid synthesis, is overexpressed in cancer but not in normal non-lipogenic tissues. FASN has been targeted, albeit no such inhibitor has been approved. Proton pump inhibitors (PPIs), approved for digestive disorders, were found to inhibit FASN with anticancer activities in attempting to repurpose Food and Drug Administration-approved drugs.