Project description:We have identified GATA-3 as a critical regulator of luminal cell differentiation in the mammary gland. Acute loss of GATA-3 in the adult mammary gland leads to an expansion of an undifferentiated luminal epithelium and the formation of a multi-layered epithelium. Here we report microarray analysis of mammary glands that have undergone acute loss of GATA-3 Keywords: genetic modification
Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
Project description:We have identified GATA-3 as a critical regulator of luminal cell differentiation in the mammary gland. Acute loss of GATA-3 in the adult mammary gland leads to an expansion of an undifferentiated luminal epithelium and the formation of a multi-layered epithelium. Here we report microarray analysis of mammary glands that have undergone acute loss of GATA-3 Adult GATA-3flox/flox; WAP-rtTA-Cre and GATA-flox/+; WAP-rtTA-Cre mice were administered doxyxcline for 5 days and their mammary glands harvested. Total RNA was extracted by the Trizol method. Het mammary gland total RNA was labeled with Cy5 while Null mammary gland total RNA was labeled with Cy3. Microarray hybridization was performed on spotted oligonucleotide microarrays with 38,000 features. Lowess print-tip normalization and analysis was performed on the Acuity software package (V 4.0)
Project description:Rank signaling regulates mammary gland development and epithelial cell differentiation. Rank receptor is expressed by mammary basal and luminal populations, but unlike that of luminal, the contribution of basal Rank signaling to mammary gland homeostasis remains poorly studied. Combining timely-regulated, basal-specific Rank expression with lineage tracing strategies we unveiled that Rank signaling controls basal cell identity in postnatal mammary glands. Enhanced basal Rank disrupts basal and luminal cell identity, resulting in aberrant luminal-like differentiation of basal cells, defective lactation and the appearance of premalignant lesions composed of a basal-derived hybrid population with luminal/alveolar features, which ultimately generates basal and luminal breast adenocarcinomas. Mechanistically, phospho-proteomic, transcriptomic and chromatin analyses support that basal Rank activation triggers the loss of tumor suppressive epigenetic regulators, leading to chromatin remodeling, disruption of basal identity and tumorigenesis. We uncover a basal Rank gene signature that can be predictive of progression from in situ to invasive adenocarcinomas and associates with poor prognosis in breast cancer patients, particularly in those diagnosed with luminal adenocarcinomas, underlining the clinical relevance of our findings. Our results reinforce the idea that basal lineage infidelity triggered by Rank signaling contribute to generation from pre-invasive lesions and transition to invasive breast cancer.