Overexpressed genes associated with hormones in terminal ductal lobular units identified by global transcriptome analysis: An insight into the anatomic origin of breast cancer
Abstract:Although human breast ducts and terminal ductal lobular units (TDLUs) share the same cell types, ample evidence shows that TDLUs are the predominant site for the origin of breast cancer. Yet, there is still limited information concerning the molecular mechanisms. Analysis of transcriptomic profiles in TDLUs may provide insight into early breast tumorigenesis. We compared genome-wide expression profiles of 8 matched sets of breast main duct and TDLU samples, using significance analysis of microarray (SAM) softw… Show more
“…The TDLU is considered to be the predominant site of the origin of breast cancer. 12 The vast majority of breast cancers are carcinomas that arise in the epithelium and include in-situ and invasive ductal and invasive lobular carcinoma. Gene expression studies have indicated that hormone-related pathways are highly enriched in the TDLU, including various hormone-related genes that are associated with breast carcinogenesis.…”
Section: Immune Cells In the Normal Breastmentioning
confidence: 99%
“…It has been proposed that the imbalanced hormone-reactions may result in the early onset of neoplastic transformation that occurs mostly in breast TDLUs. 12 The breast ducts are surrounded by stroma that consists of extracellular matrix (ECM), fibroblasts, adipocytes, immune cells, microbiome, and blood vessels. The breast ducts and stroma together comprise the breast microenvironment.…”
Section: Immune Cells In the Normal Breastmentioning
confidence: 99%
“…The anatomical distribution of immune cells in normal breast tissue and their relationship to epithelial cells is depicted in Figure 1. The presence of the immune cells in the in TDLU places them at the predominant site of the origin of breast cancer -TDLU epithelial 12 ; this close proximity provides an important opportunity for the immune cells to influence the behavior of epithelial cells. Zumwalde et al, 3 using flow cytometry of breast tissue organoids from reduction mammoplasty specimens, reported that CD8 þ cells represented 75% of CD3 þ cells; essentially all of the CD8a þ cells expressed CD8 þ b, indicating they were distinct from intestinal intraepithelial cells, which are CD8 þ aa.…”
Section: Immune Cells In the Normal Breastmentioning
Immune cells are present in normal breast tissue and in breast carcinoma. The nature and distribution of the immune cell subtypes in these tissues are reviewed to promote a better understanding of their important role in breast cancer prevention and treatment. We conducted a review of the literature to define the type, location, distribution, and role of immune cells in normal breast tissue and in in situ and invasive breast cancer. Immune cells in normal breast tissue are located predominantly within the epithelial component in breast ductal lobules. Immune cell subtypes representing innate immunity (NK, CD68 þ , and CD11c þ cells) and adaptive immunity (most commonly CD8 þ , but CD4 þ and CD20 þ as well) are present; CD8 þ cells are the most common subtype and are primarily effector memory cells. Immune cells may recognize neoantigens and endogenous and exogenous ligands and may serve in chronic inflammation and immunosurveillance. Progression to breast cancer is characterized by increased immune cell infiltrates in tumor parenchyma and stroma, including CD4 þ and CD8 þ granzyme B þ cytotoxic T cells, B cells, macrophages and dendritic cells. Tumor-infiltrating lymphocytes in breast cancer may serve as prognostic indicators for response to chemotherapy and for survival. Experimental strategies of adoptive transfer of breast tumor-infiltrating lymphocyte may allow regression of metastatic breast cancer and encourage development of innovative T-cell strategies for the immunotherapy of breast cancer. In conclusion, immune cells in breast tissues play an important role throughout breast carcinogenesis. An understanding of these roles has important implications for the prevention and the treatment of breast cancer.
“…The TDLU is considered to be the predominant site of the origin of breast cancer. 12 The vast majority of breast cancers are carcinomas that arise in the epithelium and include in-situ and invasive ductal and invasive lobular carcinoma. Gene expression studies have indicated that hormone-related pathways are highly enriched in the TDLU, including various hormone-related genes that are associated with breast carcinogenesis.…”
Section: Immune Cells In the Normal Breastmentioning
confidence: 99%
“…It has been proposed that the imbalanced hormone-reactions may result in the early onset of neoplastic transformation that occurs mostly in breast TDLUs. 12 The breast ducts are surrounded by stroma that consists of extracellular matrix (ECM), fibroblasts, adipocytes, immune cells, microbiome, and blood vessels. The breast ducts and stroma together comprise the breast microenvironment.…”
Section: Immune Cells In the Normal Breastmentioning
confidence: 99%
“…The anatomical distribution of immune cells in normal breast tissue and their relationship to epithelial cells is depicted in Figure 1. The presence of the immune cells in the in TDLU places them at the predominant site of the origin of breast cancer -TDLU epithelial 12 ; this close proximity provides an important opportunity for the immune cells to influence the behavior of epithelial cells. Zumwalde et al, 3 using flow cytometry of breast tissue organoids from reduction mammoplasty specimens, reported that CD8 þ cells represented 75% of CD3 þ cells; essentially all of the CD8a þ cells expressed CD8 þ b, indicating they were distinct from intestinal intraepithelial cells, which are CD8 þ aa.…”
Section: Immune Cells In the Normal Breastmentioning
Immune cells are present in normal breast tissue and in breast carcinoma. The nature and distribution of the immune cell subtypes in these tissues are reviewed to promote a better understanding of their important role in breast cancer prevention and treatment. We conducted a review of the literature to define the type, location, distribution, and role of immune cells in normal breast tissue and in in situ and invasive breast cancer. Immune cells in normal breast tissue are located predominantly within the epithelial component in breast ductal lobules. Immune cell subtypes representing innate immunity (NK, CD68 þ , and CD11c þ cells) and adaptive immunity (most commonly CD8 þ , but CD4 þ and CD20 þ as well) are present; CD8 þ cells are the most common subtype and are primarily effector memory cells. Immune cells may recognize neoantigens and endogenous and exogenous ligands and may serve in chronic inflammation and immunosurveillance. Progression to breast cancer is characterized by increased immune cell infiltrates in tumor parenchyma and stroma, including CD4 þ and CD8 þ granzyme B þ cytotoxic T cells, B cells, macrophages and dendritic cells. Tumor-infiltrating lymphocytes in breast cancer may serve as prognostic indicators for response to chemotherapy and for survival. Experimental strategies of adoptive transfer of breast tumor-infiltrating lymphocyte may allow regression of metastatic breast cancer and encourage development of innovative T-cell strategies for the immunotherapy of breast cancer. In conclusion, immune cells in breast tissues play an important role throughout breast carcinogenesis. An understanding of these roles has important implications for the prevention and the treatment of breast cancer.
“…These three pathways are intimately connected in a feedback loop: EMT and up-regulation of the inflammatory response leads to secretion of inflammatory mediators including cytokines, chemokines, and matrix MMPs that create a pro-tumor microenvironment that enhances angiogenesis, induces EMT, and maintains inflammation through paracrine and autocrine effects (Figure 4B) (24). For BRCA, there was AFR up-regulation of 12 genes involved in response to estrogen and several genes involved in KRAS activation including HSD11B2, which is implicated in hormone metabolism and response and over-expressed in both breast cancer cell lines and breast tumors (Supplementary Table S6) (25). Estrogen has also been linked to breast cancer for its potential role as a mitogen stimulating cell division of breast tissue or as a carcinogen (26).…”
While overall cancer mortality has steadily decreased in recent decades, cancer health disparities among racial and ethnic population groups persist. Here we studied the relationship between cancer survival disparities (CSD), genetic ancestry (GA), and tumor molecular signatures across 33 cancers in a cohort of 9,818 patients. GA correlated with race and ethnicity but showed observable differences in effects on CSD, with significant associations identified in four cancer types: breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), and skin cutaneous carcinoma (SKCM). Differential gene expression and methylation between ancestry groups associated cancer-related genes with CSD, of which seven protein-coding genes (PAQR6, LIME1, SAP25, MXD3, CCER2, RFLNA, and CTSW) significantly interacted with GA and exacerbated observed survival disparities.These findings indicated that regulatory changes mediated by epigenetic mechanisms have a greater contribution to CSD than population-specific mutations. Overall, we uncovered various molecular mechanisms through which GA might impact CSD, revealing potential population-specific therapeutic targets for groups disproportionately burdened by cancer.
Over the past decades, luminal epithelial cell lineage has gained considerable attraction as the functionally milk-secreting units and as the most fruitful acreage for breast cancer launching. Recognition of the effective involvement of the myoepithelial cells in mammary gland development and in hampering tumorigenesis has renewed the interest in investigating the biological roles of this second main mammary lineage. The human breast is made up of an extensively branching ductal system intervening by copious lobular units. The ductal system is coated by a chain of luminal epithelial cells (LECs) situated on a layer of myoepithelial cells (MECs) and encompassed by a distinguished basement membrane. Ductal contractility during lactation is a well-known function delivered by the MECs however this is not the only assignment mediated by these cellular populations. It has been well appreciated that the MECs exhibit a natural paracrine power in defeating cancer development and advancement. MECs were found to express numerous proteinase inhibitors, anti-angiogenic factors, and tumour suppressors proteins. Additionally, MECs contributed effectively to maintaining the right luminal cells' polarization and further separating them from the adjacent stroma by making an integrated fence. Indeed, disruption of the MECs layer was reported to facilitate the invasion of the cancer cells to the surrounding stroma. Nonetheless, MECs were also found to exhibit cancer-promoting effects and provoke tumour invasion and dissemination by displaying distinct cancer chemokines. Herein in this review, we aimed to address the roles delivered by MECs in breast cancer progression and decipher the molecular mechanisms regulating proper MECs’ physiology, integrity, and terminal differentiation.
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