Analysis of phenolic compounds of interest in metabolism.

The transcription factor Gata-3 is a defining marker of the 'luminal' subtypes of breast cancer. To gain insight into the role of Gata-3 in breast epithelial development and oncogenesis, we have explored its normal function within the mammary gland by conditionally deleting Gata-3 at different stages of development. We report that Gata-3 has essential roles in the morphogenesis of the mammary gland in both the embryo and adult. Through the discovery of a novel marker (beta3-integrin) of luminal progenitor cells and their purification, we demonstrate that Gata-3 deficiency leads to an expansion of luminal progenitors and a concomitant block in differentiation. Remarkably, introduction of Gata-3 into a stem cell-enriched population induced maturation along the alveolar luminal lineage. These studies provide evidence for the existence of an epithelial hierarchy within the mammary gland and establish Gata-3 as a critical regulator of luminal differentiation.

Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation

Ascorbic acid in aromatic hydroxylation. I. A model system for aromatic hydroxylation.

The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A key event in this process is the deregulation of normal self-renewal in these cells. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. We will discuss the important implications of this mammary tumour stem-cell model.

/pdf/stem-cells-in-normal-breast-development-and-breast-cancer-2n4ibkw956.pdf

Stem cells in normal breast development and breast cancer

Abstract.  The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem‐cell self‐renewal and differentiation. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A key event in this process is the deregulation of normal self‐renewal in these cells. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. We will discuss the important implications of this mammary tumour stem‐cell model.

Stem cells in normal breast development and breast cancer: Stem cells in normal breast development and breast cancer

LMO4 belongs to a family of LIM-only transcriptional regulators, the first two members of which are oncoproteins in acute T cell leukemia. We have explored a role for LMO4, initially described as a human breast tumor autoantigen, in developing mammary epithelium and breast oncogenesis. Lmo4 was expressed predominantly in the lobuloalveoli of the mammary gland during pregnancy. Consistent with a role in proliferation, forced expression of this gene inhibited differentiation of mammary epithelial cells. Overexpression of LMO4 mRNA was observed in 5 of 10 human breast cancer cell lines. Moreover, in situ hybridization analysis of 177 primary invasive breast carcinomas revealed overexpression of LMO4 in 56% of specimens. Immunohistochemistry confirmed overexpression in a high percentage (62%) of tumors. These studies imply a role for LMO4 in maintaining proliferation of mammary epithelium and suggest that deregulation of this gene may contribute to breast tumorigenesis.

https://www.pnas.org/content/pnas/98/25/14452.full.pdf

The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer

Studies in detoxication. 19. The metabolism of benzene. I. (a) The determination of phenol in urine with 2:6-dichloroquinonechloroimide. (b) The excretion of phenol, glucuronic acid and ethereal sulphate by rabbits receiving benzene and phenol. (c) Observations on the determination of catechol, quinol and muconic acid in urine

/pdf/studies-in-detoxication-23-the-fate-of-aniline-in-the-rabbit-4qx33f76dp.pdf

Studies in detoxication. 23. The fate of aniline in the rabbit

Studies in detoxication. 20. The metabolism of benzene. II. The isolation of phenol, catechol, quinol and hydroxyquinol from the ethereal sulphate fraction of the urine of rabbits receiving benzene orally.

/pdf/studies-in-detoxication-22-the-metabolism-of-phenacetin-p-11mh1utfgf.pdf

R. T. Williams

Papers

The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer

Studies in detoxication. 23. The fate of aniline in the rabbit

Studies in detoxication. 20. The metabolism of benzene. II. The isolation of phenol, catechol, quinol and hydroxyquinol from the ethereal sulphate fraction of the urine of rabbits receiving benzene orally.

Studies in detoxication. 22. The metabolism of phenacetin (p-ethoxyacetanilide) in the rabbit and a further observation on acetanilide metabolism.