BACKGROUND: Breast cancer can be broadly categorized into two groups depending on the cell type affected. Luminal-type tumors are typically estrogen receptor (ER) positive that are associated with better survival and respond to hormone therapies whereas basal-like tumors are ER negative, more aggressive, and associated with a poor prognosis. GATA3 is a transcription factor well studied for its role as a master regulator of cellular differentiation and stem cell self renewal. Loss of Gata3 in mouse mammary glands blocks luminal cell differentiation and induces growth defects, and low levels of GATA3 are associated with basal-like and metastatic human breast cancers with epithelial-to-mesenchymal transition (EMT). Importantly, luminal cells have been shown to be the origin of some basal-like breast cancers. Due to the proliferation defects caused by GATA3 deficiency, it remains elusive how loss of function of GATA3 contributes to breast cancers development and progression. METHODS: We previously demonstrated that p18Ink4c (p18), a cell cycle inhibitor, is a downstream target of GATA3 in regulating mammary luminal cell proliferation and loss of p18 leads to luminal type tumorigenesis. To test the role of Gata3 deficiency in tumorigenesis, we generated p18-/-;Gata3+/- mice. Mammary gland development and tumorigenesis were characterized in vivo using a panel of cellular and molecular assays. Results were further confirmed in vitro with well established cell lines. RESULTS: Loss of p18 rescued mammary growth defects caused by Gata3 heterozygosity. Gata3 heterozygosity impaired luminal, but promoted basal gene expression in mammary epithelial cells. Gata3 heterozygosity in p18 null mice accelerated spontaneous mammary tumorigenesis, reducing the average latency of tumor onset. More importantly, Gata3 heterozygosity transformed the luminal type tumors of p18 null mice into heterogeneous basal-like breast cancers with activated EMT. Conversely, reintroduction of GATA3 inhibited tumor growth and reduced expression of EMT markers in basal-like tumor xenografts. We discovered that expression of GATA3 and Vimentin, an EMT marker, is inversely related in human breast cancers. CONCLUSION: Our data indicates that GATA3 promotes luminal but suppresses basal cell differentiation in the mammary gland and in tumor development. Mechanisms underlying the role of GATA3 in suppressing basal-like tumor development are under investigation.BACKGROUND: Breast cancer can be broadly categorized into two groups depending on the cell type affected. Luminal-type tumors are typically estrogen receptor (ER) positive that are associated with better survival and respond to hormone therapies whereas basal-like tumors are ER negative, more aggressive, and associated with a poor prognosis. GATA3 is a transcription factor well studied for its role as a master regulator of cellular differentiation and stem cell self renewal. Loss of Gata3 in mouse mammary glands blocks luminal cell differentiation and induces growth defects, and low levels of GATA3 are associated with basal-like and metastatic human breast cancers with epithelial-to-mesenchymal transition (EMT). Importantly, luminal cells have been shown to be the origin of some basal-like breast cancers. Due to the proliferation defects caused by GATA3 deficiency, it remains elusive how loss of function of GATA3 contributes to breast cancers development and progression. METHODS: We previously demonstrated that p18Ink4c (p18), a cell cycle inhibitor, is a downstream target of GATA3 in regulating mammary luminal cell proliferation and loss of p18 leads to luminal type tumorigenesis. To test the role of Gata3 deficiency in tumorigenesis, we generated p18-/-;Gata3+/- mice. Mammary gland development and tumorigenesis were characterized in vivo using a panel of cellular and molecular assays. Results were further confirmed in vitro with well established cell lines. RESULTS: Loss of p18 rescued mammary growth defects caused by Gata3 heterozygosity. Gata3 heterozygosity impaired luminal, but promoted basal gene expression in mammary epithelial cells. Gata3 heterozygosity in p18 null mice accelerated spontaneous mammary tumorigenesis, reducing the average latency of tumor onset. More importantly, Gata3 heterozygosity transformed the luminal type tumors of p18 null mice into heterogeneous basal-like breast cancers with activated EMT. Conversely, reintroduction of GATA3 inhibited tumor growth and reduced expression of EMT markers in basal-like tumor xenografts. We discovered that expression of GATA3 and Vimentin, an EMT marker, is inversely related in human breast cancers. CONCLUSION: Our data indicates that GATA3 promotes luminal but suppresses basal cell differentiation in the mammary gland and in tumor development. Mechanisms underlying the role of GATA3 in suppressing basal-like tumor development are under investigation. Citation Format: Pei X-H, Chan HL, Liu S, Scott A, Pimentel E, Slingerland J, Robbins D, Capobianco A, Bai F. GATA3 inhibits breast basal-like tumorigenesis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-08-08.

trachelectomy with preservation of the entire uterus, the majority of the vagina, and negative surgical margins were obtained. She recovered well and is currently undergoing chemotherapy. Conclusions To our knowledge, this is the youngest patient having undergone an abdominal trachelectomy. This approach appears to be safe in the pediatric population.

BACKGROUND: Breast cancer is mainly divided into estrogen receptor (ER)-positive luminal and ER-negative basal-like tumors. Luminal-type tumors are associated with better survival and respond to hormone therapies whereas basal-like tumors are more aggressive and associated with a poor prognosis. Mammary epithelia are mainly composed of luminal and basal cells that are maintained by luminal and basal progenitors, respectively. The maintenance of luminal cell fate is orchestrated by networks of transcription factors, including BRCA1 and GATA3. Functional loss of BRCA1 by germline or somatic mutation or by promoter methylation is associated with more than one third of basal-like breast cancers. GATA3 expression is reduced in basal-like breast cancers and cancers that metastasize. Overexpression of GATA3 in cancer cells inhibits tumor formation. Deletion of Brca1 or Gata3 in mice results in early lethality or growth defects. How BRCA1 and GATA3 suppress breast cancer remains elusive. METHODS: We generated mice lacking Brca1 or Gata3 in mammary epithelia. Due to the proliferative defects and induction of p18Ink4c (p18), an inhibitor of CDK4/6, in mammary epithelial cells of these mice, we then generated mice lacking Brca1 or Gata3 in p18 deficient mammary epithelia. We determined spontaneous mammary tumor development in mutant mice and the mechanisms underlying the role of Brca1 and Gata3 in suppressing tumorigenesis and progression. RESULTS: Depletion of Brca1 or Gata3 led to growth defects of mammary epithelial cells, which was rescued by loss of p18. Depletion of Brca1 or Gata3 in a p18 null background induced heterogeneous mammary tumors with less luminal and more basal-like features and accelerated metastasis. Deletion of Brca1 eliminated Gata3 expression in human and mouse mammary tissues and cells. How Brca1 interacts with Gata3 to control mammary tumor development and progression is currently under investigation. CONCLUSION: Our results suggest that loss of function of either Brca1 or Gata3 induces basal-like mammary tumors in p18 deficient background. Citation Format: Pei X-H, Chan HL, Zhang L, Wang C, Robbins DJ, Capobianco T, Bai F. Loss of function of Brca1 or Gata3 induces basal-like breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-08-01.