Biology subjects

Althouse, S. K.

Publications and source records attributed to Althouse, S. K..

3 recordsLinked to original sources

bioRxiv2022

Influence of genetic ancestry on breast stromal cells provides biologic basis for 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 the ductal epithelial cells in the normal breast of women of African Ancestry (AA) compared to European Ancestry (EA). By establishing and characterizing cell lines corresponding to these cells and validating in vitro findings with tissue microarrays of healthy breast tissue from AA, EA and Latina Ancestry (LA) women, we demonstrate that these cells have the properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFR. PROCR+/ZEB1+/PDGFR+ cells, hence renamed as PZP cells, are enriched in the normal breast tissues of AA compared to EA or LA women. In vitro, PZP cells trans-differentiated into adipocytes or osteocytes. In co-culture conditions, PZP:epithelial cell communication resulted in luminal epithelial cells acquiring basal/stem cell characteristics and increased expression of IL-6 suggesting the impact of this communication on breast epithelial hierarchy and the microenvironment. Consistent with this possibility, the level of phospho-STAT3, which is a downstream target of IL-6, was higher in the normal and cancerous breast tissues of AA compared to EA women. PZP cells transformed with HRasG12V {+/-} SV40-T/t antigens generated metaplastic carcinoma in NSG mice suggesting that these cells could be the cell-of-origin of metaplastic breast cancers. Collectively, these results identify a stromal cell component that could influence the biology of breast cancer in AA women.

cancer biology↗

bioRxiv2021

Aberrant epigenetic and transcriptional events associated with breast cancer risk

BackgroundGenome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N=146, median age=39 years) were processed for both methylome (MethylCap) and transcriptome (Illuminas HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation. ResultsTranscriptomic analysis identified 69 differentially expressed genes between women at either high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR<0.05 and fold change[≥]2. The majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR<0.01) and primary epithelial cells (p<0.05) from high-risk breasts. Moreover, 1698 DNA methylation aberrations were identified in high-risk breast tissues (FDR<0.05), partially overlapped with cancer-related signatures and correlated with transcriptional changes (p<0.05, r[≤]0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified. ConclusionsNormal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.

cancer biology↗

bioRxiv2020

A single cell atlas of the healthy breast tissues reveal clinically relevant clusters of breast epithelial cells

SummarySingle cell RNA sequencing is an evolving field to elucidate cellular architecture of adult organs. Using normal breast tissues from healthy volunteers and a rapid procurement/processing/sequencing protocol, 13 breast epithelial cell clusters were identified. Approximately 90% of breast cancers were enriched for cell-of-origin signatures derived from differentiated luminal clusters and two minor luminal progenitor clusters. Expression of cell cycle and chromosome segregation-related genes were higher in one of the minor clusters and breast tumors with this cluster signature displayed the highest mutation rate and poor outcome. We identified TBX3 and PDK4 as genes co-expressed with estrogen receptor (ER) in the normal breasts and their expression analyses in >550 breast cancers enabled prognostically relevant cell-of-origin based subclassification of ER+ breast cancers.Significance This study elucidates different epithelial cell types of the normal breasts and identifies a minor subpopulation of cells from which the majority of breast cancers may originate. This observation should help to develop methods to characterize breast tumors based on cell-of-origin. Although it was suggested that intrinsic subtypes of breast cancers have distinct cells of origins, this study suggests multiple cell-of-origin for an intrinsic subtype of breast cancer, including for hormone responsive breast cancers. Cell-of-origin signatures allowed survival-associated subclassification of intrinsic subtypes. Critically, this normal breast cell atlas would allow for the classification of genes differentially expressed in a breast tumor compared to normal breast due to the cell-of-origin of tumor and those that are acquired due to genomic aberrations.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗