Breast cancer prevention by short-term inhibition of TGFβ signaling
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE184095 | GEO | 2022/11/02
REPOSITORIES: GEO
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Project description:Emerging data indicate that breast epithelial stem cells and progenitors, particularly those in the luminal epithelial cell lineage, are the cells-of-origin of breast carcinomas, and factors that influence breast cancer risk may alter the number and/or properties of these cells. We hypothesize that a subset of p27+ cells represent hormone-responsive progenitors that are quiescent due to the high activity of TGFβ signaling in these cells. The Estrogen-induced mammary tumor model in ACI inbred rats is physiologically relevant rodent model of breast cancer. In the present study we successfully generated Cdkn1b knockout ACI rats and performed comprehensive phenotypic assessment and RNAseq profiling using FACS sorted basal (CD24+CD29high) and luminal (CD24+CD29low) cell populations to characterize Cdkn1b+/+ and Cdkn1b-/- females in prepubertal and adult cohorts. We found that p27KO rats exhibited mammary differentiation phenotype and reduced numbers of mammary epithelial progenitor pool, Interestingly, p27 ablation has the most pronounced effect on luminal progenitor cell gene expression, and milk protein genes and pStat5 were dramatically upregulated, while PR and FoxA1 were greatly downregulated in Cdkn1b-/- luminal cells. Further characterization of mammary glands of prepubertal Cdkn1b knockout rats by fat pad transplantation illustrated p27 deletion in the mammary cancer susceptible ACI rat strain induced mammary epithelial cell differentiation through cell non-autonomous mechanisms.
2019-02-11 | GSE116831 | GEO
Project description:We are using the ACI rat model of 17beta-estradiol induced mammary cancer to define the mechanisms through which estrogens contribute to breast cancer development; identify and functionally characterize the genetic variants that determine susceptibility; and define the hormone-gene-environment interactions that influence development of mammary cancer in this physiologically relevant rat model. Female ACI rats are uniquely susceptible to development of mammary cancer when treated continuously with physiologic levels of 17beta-estradiol. Induction of mammary cancer in female ACI rats occurs through a mechanism that is largely dependent upon estrogen receptor-alpha. Interval mapping analyses of progeny generated in intercrosses between susceptible ACI rats and resistant Brown Norway (BN) rats revealed seven quantitative trait loci (QTL), designated Emca3 (Estrogen-induced mammary cancer) through Emca9, each of which harbors one or more genetic determinants of mammary cancer susceptibility. Genes that reside within Emca8 on RNO5 and were differentially expressed between 17beta-estradiol treated ACI and ACI.BN-Emca8 congenic rats were identified as Emca8 candidates.
2013-02-08 | GSE39788 | GEO
Project description:We are using the ACI rat model of 17beta-estradiol induced mammary cancer to define the mechanisms through which estrogens contribute to breast cancer development; identify and functionally characterize the genetic variants that determine susceptibility; and define the hormone-gene-environment interactions that influence development of mammary cancer in this physiologically relevant rat model. Female ACI rats are uniquely susceptible to development of mammary cancer when treated continuously with physiologic levels of 17beta-estradiol. Induction of mammary cancer in female ACI rats occurs through a mechanism that is largely dependent upon estrogen receptor-alpha. Interval mapping analyses of progeny generated in intercrosses between susceptible ACI rats and resistant Brown Norway (BN) rats revealed seven quantitative trait loci (QTL), designated Emca3 (Estrogen-induced mammary cancer) through Emca9, each of which harbors one or more genetic determinants of mammary cancer susceptibility. Genes that reside within Emca8 on RNO5 and were differentially expressed between 17beta-estradiol treated ACI and ACI.BN-Emca8 congenic rats were identified as Emca8 candidates. Two groups of 17beta-estradiol treated female rats were compared. Five ACI and five BN.ACI-Emca8 rats were treated with 17beta-estradiol for 12 weeks. Total RNA was isolated from the mammary glands of these animals, labeled, and hybridized to Affymetrix Rat Genome 230 2.0 Arrays (Affymetrix Inc.). Significantly differentially expressed genes were found between these groups.
2013-02-08 | E-GEOD-39788 | biostudies-arrayexpress
Project description:We are using ACI and BN rats, which differ markedly in their susceptibility to 17beta-Estradiol (E2)-induced mammary cancer, to identify genetic variants and environmental factors that determine mammary cancer susceptibility. The objective of this study was to characterize the cellular and molecular responses to E2 in the mammary glands of ACI and BN rats to identify qualitative and quantitative phenotypes that associate with and/or may confer differences in susceptibility to mammary cancer. Female ACI and BN rats were treated with E2 for 1, 3 or 12 weeks and cell proliferation, apoptosis, differentiation and gene expression were evaluated. The luminal epithelium of ACI rats exhibited a rapid and sustained proliferative response to E2. By contrast, the proliferative response exhibited by the mammary epithelium of BN rats was restrained and transitory. Moreover, the epithelium of BN rats appeared to undergo differentiation in response to E2, as evidenced by production of milk proteins as well as luminal ectasia and associated changes in the extracellular matrix (ECM). Marked differences in expression of genes that encode proteins with well-defined roles in mammary gland development (Pgr, Wnt4, Tnfsf11, Prlr, Stat5a, Areg, Gata3), differentiation and milk production (Lcn2, Spp1), regulation of extracellular environment (Mmp7, Mmp9), and cell-cell or cell-ECM interactions (Cd44, Cd24, Cd52) were observed. We propose that these cellular and molecular phenotypes are heritable and may underlie, at least in part, the differences in mammary cancer susceptibility exhibited by ACI and BN rats.
2014-02-01 | GSE49548 | GEO
Project description:We are using ACI and BN rats, which differ markedly in their susceptibility to 17beta-Estradiol (E2)-induced mammary cancer, to identify genetic variants and environmental factors that determine mammary cancer susceptibility. The objective of this study was to characterize the cellular and molecular responses to E2 in the mammary glands of ACI and BN rats to identify qualitative and quantitative phenotypes that associate with and/or may confer differences in susceptibility to mammary cancer. Female ACI and BN rats were treated with E2 for 1, 3 or 12 weeks and cell proliferation, apoptosis, differentiation and gene expression were evaluated. The luminal epithelium of ACI rats exhibited a rapid and sustained proliferative response to E2. By contrast, the proliferative response exhibited by the mammary epithelium of BN rats was restrained and transitory. Moreover, the epithelium of BN rats appeared to undergo differentiation in response to E2, as evidenced by production of milk proteins as well as luminal ectasia and associated changes in the extracellular matrix (ECM). Marked differences in expression of genes that encode proteins with well-defined roles in mammary gland development (Pgr, Wnt4, Tnfsf11, Prlr, Stat5a, Areg, Gata3), differentiation and milk production (Lcn2, Spp1), regulation of extracellular environment (Mmp7, Mmp9), and cell-cell or cell-ECM interactions (Cd44, Cd24, Cd52) were observed. We propose that these cellular and molecular phenotypes are heritable and may underlie, at least in part, the differences in mammary cancer susceptibility exhibited by ACI and BN rats. Two groups of 17beta-estradiol treated female rats were compared. Five ACI and five BN rats were treated with 17beta-estradiol for 12 weeks. Total RNA was isolated from the mammary glands of these animals, labeled, and hybridized to Affymetrix Rat Genome 230 2.0 Arrays (Affymetrix Inc.). Significantly differentially expressed genes were found between these groups.
2014-02-01 | E-GEOD-49548 | biostudies-arrayexpress
Project description:Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. Defects in mammary epithelial cell differentiation have been previously recognized in germline BRCA1/2 mutation carriers even before cancer incidence. However, the underlying mechanism is largely unknown. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells may differ from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. Implications: These results suggest alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.
2023-10-11 | GSE234017 | GEO
Project description:ABSTRACT: Obesity is responsible for decreased overall survival for breast cancer patients. Here, we describe the generation, characterization and application of a novel murine mammary tumor initiating cell model (M-Wnt) that recapitulates the claudin-low subtype of human breast cancer and permits the study of TIC’s in wild-type, immunocompetent mice. M-Wnt cells readily form mammospheres in suspension culture, express markers consistent with epithelial-to-mesenchymal transition (EMT), and generate claudin-low mammary tumors when as few as 50 cells are orthotopically injected. Using the M-Wnt cell lines in tandem with a more basal-like epithelial breast cancer cell line, E-Wnt, we found that diet induced obesity significantly downregulates epithelial markers, such as E-cadherin, and upregulates mesenchymal markers including fibronectin, N-cadherin, SNAIL, Oct-4, and TGF-b. This reveals a previously unidentified link between energy balance and EMT. The ability of calorie restriction (CR) to reverse EMT, upregulate epithelial markers and downregulate mesenchymal markers indicates the plasticity of the TICs, as well as the potential importance of lifestyle modifications as cancer prevention strategies. 28 array samples
2012-06-29 | E-GEOD-28713 | biostudies-arrayexpress
Project description:Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER+ mature luminal mammary epithelial cells and ER+ breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancer-specific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER+ breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics. SIGNIFICANCE STATEMENT: Abnormal estrogen receptor (ER) signaling drives the majority of breast cancers and is targeted by endocrine therapies. However, in normal breast tissue, ER signaling has been demonstrated to promote benign functions such as development and differentiation. Using genomic techniques to characterize ER function in normal breast and breast tumors, this study reveals differential patterns of ER signaling, suggesting that normal ER signaling is lost and tumorigenic ER signaling gained during breast tumor formation. Better understanding of this process can aid the development of improved breast cancer prevention strategies and therapies.
2019-05-27 | GSE99680 | GEO
Project description:Breast cancer prevention by short-term inhibition of TGFβ signaling
| PRJNA763177 | ENA
Project description:The role of diet in the prevention of breast cancer is widely accepted, yet little is known on how early dietary effects mitigate adult cancer risk. Soy consumption is associated with reduced breast cancer risk in women, an effect largely attributed to the soy isoflavone genistein (GEN). We previously showed lower chemically-induced mammary tumor incidence in young adult rats with lifetime dietary intake of soy protein isolate (SPI), a highly refined soy product in infant formula, than in those fed the control diet Casein (CAS). To gain insight into signaling pathways underlying dietary tumor protection, we performed genome-wide expression profiling of mammary epithelial cells from young adult rats lifetime fed CAS, SPI, or supplemental GEN-based diets. We identified mammary epithelial genes regulated by SPI (79 total) and GEN (99 total) using Affymetrix rat 230A GeneChip arrays and found minimal overlap in gene expression patterns. We showed that the regulated transcripts functionally cluster in biochemical pathways involving metabolism, immune response, signal transduction, and ion transport. We confirmed the differential expression of Wnt (Wnt5a, Sfrp2) and Notch (Notch2, Hes1) signaling components by SPI and/or GEN using QPCR. Wnt pathway inhibition by GEN was supported by lower Cyclin D1 immunoreactivity in mammary ductal epithelium of GEN relative to CAS and SPI, despite their comparable levels of membrane-localized E-cadherin and β-catenin. Identification of distinct GEN and SPI responsive genes in mammary epithelial cells may define early events contributing to tumor protection by diet relevant to the prevention of breast and other types of cancer. Experiment Overall Design: Female Sprague-Dawley rats, fed one of the three purified diets, were studied at postnatal day50. Total RNA( each RNA samples were extracted from #4 mammary gland from two animals under the same diet group) purified from non-tumor tissue within the proximal half of each colon, was used to prepare biotinylated probes, which were hybridized to Affymetrix RAE230 rat microarrays.
2007-11-29 | E-GEOD-6879 | biostudies-arrayexpress