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Regulation of in situ to invasive breast carcinoma transition.

ABSTRACT: The transition of ductal carcinoma in situ (DCIS) to invasive carcinoma is a poorly understood key event in breast tumor progression. Here, we analyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using a model of human DCIS and primary breast tumors. Progression to invasion was promoted by fibroblasts and inhibited by normal myoepithelial cells. Molecular profiles of isolated luminal epithelial and myoepithelial cells identified an intricate interaction network involving TGFbeta, Hedgehog, cell adhesion, and p63 required for myoepithelial cell differentiation, the elimination of which resulted in loss of myoepithelial cells and progression to invasion.

SUBMITTER: Hu M

PROVIDER: S-EPMC3705908 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Regulation of in situ to invasive breast carcinoma transition.

Hu Min M Yao Jun J Carroll Danielle K DK Weremowicz Stanislawa S Chen Haiyan H Carrasco Daniel D Richardson Andrea A Violette Shelia S Nikolskaya Tatiana T Nikolsky Yuri Y Bauerlein Erica L EL Hahn William C WC Gelman Rebecca S RS Allred Craig C Bissell Mina J MJ Schnitt Stuart S Polyak Kornelia K

Cancer cell 20080501 5

The transition of ductal carcinoma in situ (DCIS) to invasive carcinoma is a poorly understood key event in breast tumor progression. Here, we analyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using a model of human DCIS and primary breast tumors. Progression to invasion was promoted by fibroblasts and inhibited by normal myoepithelial cells. Molecular profiles of isolated luminal epithelial and myoepithelial cells identified an intricate interacti ...[more]

PMID: 18455123

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Immune escape in breast cancer during in situ to invasive carcinoma transition

Project description:To dissect mechanisms of immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinomas in situ (DCIS), and HER2+ and triple negative invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Analysis of gene expression profiles of T cells demonstrated enrichment for activated GZMB+MKI67+CD8+ effector T cell signatures in DCIS. TCR clonotypes also showed highest diversity in DCIS. Naïve T cell signatures predominated IDCs, especially triple negative subtypes. TIGIT and PDL1 immune checkpoint proteins showed differential expression between DCIS and IDCs with amplification of CD274 (encoding PDL1) only detected in triple negative IDCs. Our results imply that DCIS progression is limited by an anti-tumor immune response that becomes muted in invasive tumors due to selection for cancer cells and microenvironment that suppress activated T cells or no longer trigger their activation.

2017-06-28 | GSE87517 | GEO

Immune Escape in Breast Cancer During <i>In Situ</i> to Invasive Carcinoma Transition.

Project description:To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. ©2017 AACR.See related commentary by Speiser and Verdeil, p. 1062This article is highlighted in the In This Issue feature, p. 1047.

| S-EPMC5628128 | biostudies-literature

Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma.

Project description:Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling and that its loss/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, MEK1/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions.

| S-EPMC8162601 | biostudies-literature

Genomic alterations during the in situ to invasive ductal breast carcinoma transition shaped by the immune system

Project description:Genomic alterations during the in situ to invasive ductal breast carcinoma transition shaped by the immune system

2020-12-01 | GSE144020 | GEO

Progression of ductal carcinoma in situ to invasive breast cancer

Project description:Ductal carcinoma in situ (DCIS) is a precursor lesion that can give rise to invasive breast cancer (IBC). It has been proposed that both the nature of the lesion and the tumor microenvironment play key roles in progression to IBC. Here, laser capture microdissected tissue samples from epithelium and stroma in normal breast, pure DCIS, and pure IBC were employed to define key gene expression profiles associated with disease progression. Tumor and matching stroma were profiled for 9 DCIS patients, 10 IBC patients, and 3 normal breast. Differential gene expression was evaluated for paired normal stroma versus normal epitelium samples, paired DCIS stroma versus DCIS epitelium samples, paired IBC stroma versus IBC epitelium, IBC stroma versus DCIS stroma, and IBC epithelium versus DCIS epithelium.

2012-03-31 | E-GEOD-33692 | biostudies-arrayexpress

Progression of ductal carcinoma in situ to invasive breast cancer

2012-04-01 | GSE33692 | GEO

Genomic Alterations during the <i>In Situ</i> to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System.

Project description:The drivers of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. Here, we conducted an integrated genomic, transcriptomic, and whole-slide image analysis to evaluate changes in copy-number profiles, mutational profiles, expression, neoantigen load, and topology in 6 cases of matched pure DCIS and recurrent IDC. We demonstrate through combined copy-number and mutational analysis that recurrent IDC can be genetically related to its pure DCIS despite long latency periods and therapeutic interventions. Immune "hot" and "cold" tumors can arise as early as DCIS and are subtype-specific. Topologic analysis showed a similar degree of pan-leukocyte-tumor mixing in both DCIS and IDC but differ when assessing specific immune subpopulations such as CD4 T cells and CD68 macrophages. Tumor-specific copy-number aberrations in MHC-I presentation machinery and losses in 3p, 4q, and 5p are associated with differences in immune signaling in estrogen receptor (ER)-negative IDC. Common oncogenic hotspot mutations in genes including TP53 and PIK3CA are predicted to be neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition, and are associated with differences in immune signaling. We highlight both tumor and immune-specific changes in the transition of pure DCIS to IDC, including genetic changes in tumor cells that may have a role in modulating immune function and assist in immune escape, driving the transition to IDC. IMPLICATIONS: We demonstrate that the in situ to IDC evolutionary bottleneck is shaped by both tumor and immune cells.

| S-EPMC8026652 | biostudies-literature

Progression of ductal carcinoma in situ to invasive breast cancer

| S-ECPF-GEOD-33692 | biostudies-other

Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer.

Project description:Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.

| S-EPMC4480702 | biostudies-literature

Progression from ductal carcinoma in situ to invasive breast cancer: revisited.

Project description:Ductal carcinoma in situ (DCIS) is an intraductal neoplastic proliferation of epithelial cells that is separated from the breast stroma by an intact layer of basement membrane and myoepithelial cells. DCIS is a non-obligate precursor of invasive breast cancer, and up to 40% of these lesions progress to invasive disease if untreated. Currently, it is not possible to predict accurately which DCIS would be more likely to progress to invasive breast cancer as neither the significant drivers of the invasive transition have been identified, nor has the clinical utility of tests predicting the likelihood of progression been demonstrated. Although molecular studies have shown that qualitatively, synchronous DCIS and invasive breast cancers are remarkably similar, there is burgeoning evidence to demonstrate that intra-tumor genetic heterogeneity is observed in a subset of DCIS, and that the process of progression to invasive disease may constitute an 'evolutionary bottleneck', resulting in the selection of subsets of tumor cells with specific genetic and/or epigenetic aberrations. Here we review the clinical challenge posed by DCIS, the contribution of the microenvironment and genetic aberrations to the progression from in situ to invasive breast cancer, the emerging evidence of the impact of intra-tumor genetic heterogeneity on this process, and strategies to combat this heterogeneity.

| S-EPMC5528459 | biostudies-other

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