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:The GATA-type zinc-finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expression is indispensable for proliferation of mammary organoids and in vivo survival of luminal epithelial cells during mammary gland development. However, the consequences of TRPS1 loss are dependent on E-cadherin status, as combined inactivation of E-cadherin and TRPS1 causes persistent proliferation of mammary organoids and accelerated mammary tumor formation in mice. Together, our results demonstrate that TRPS1 can function as a context-dependent tumor suppressor in breast cancer, whilst being essential for growth and differentiation of normal mammary epithelial cells.