Estrogen regulates luminal progenitor cell differentiation through H19 gene expression

Although the role of estrogen signaling in breast cancer development has been extensively studied, the mechanisms that regulate the indispensable role of estrogen in normal mammary gland development have not been well studied. Because of the unavailability of culture system to maintain estrogen-receptor-positive (ERα+) cells in vitro, the molecular mechanisms that regulate estrogen/ERα signaling in the normal human breast are unknown. In the present study, we examined the effects of estrogen signaling on ERα+ human luminal progenitors using a modified matrigel assay and found that estrogen signaling increased the expansion potential of these progenitors. Furthermore, we found that blocking ERα attenuated luminal progenitor expansion and decreased the luminal colony-forming potential of these progenitors. Additionally, blocking ERα decreased H19 expression in the luminal progenitors and led to the development of smaller luminal colonies. We further showed that knocking down the H19 gene in the luminal progenitors significantly decreased the colony-forming potential of the luminal progenitors, and this phenotype could not be rescued by the addition of estrogen. Lastly, we explored the clinical relevance of the estrogen–H19 signaling axis in breast tumors and found that ERα+ tumors exhibited a higher expression of H19 as compared with ERα− tumors and that H19 expression showed a positive correlation with ERα expression in those tumors. Taken together, the present results indicate that the estrogen–ERα–H19 signaling axis plays a role in regulating the proliferation and differentiation potentials of the normal luminal progenitors and that this signaling network may also be important in the development of ER+ breast cancer tumors.

[1]  J. Visvader,et al.  Mammary stem cells and the differentiation hierarchy: current status and perspectives , 2014, Genes & development.

[2]  Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium , 2014, Breast Cancer Research.

[3]  J. Graham,et al.  Progesterone stimulates progenitor cells in normal human breast and breast cancer cells , 2014, Breast Cancer Research and Treatment.

[4]  Rong Yin,et al.  Long noncoding RNA: an emerging paradigm of cancer research , 2013, Tumor Biology.

[5]  A. Raouf,et al.  In vitro methods to culture primary human breast epithelial cells. , 2013, Methods in molecular biology.

[6]  J. Graham,et al.  Progesterone and estrogen receptors segregate into different cell subpopulations in the normal human breast , 2012, Molecular and Cellular Endocrinology.

[7]  M. Kyba,et al.  The H19 lincRNA is a developmental reservoir of miR-675 which suppresses growth and Igf1r , 2012, Nature Cell Biology.

[8]  I. Ellis,et al.  Differential oestrogen receptor binding is associated with clinical outcome in breast cancer , 2011, Nature.

[9]  T. Scheper,et al.  Transcriptome analysis. , 2012, Advances in biochemical engineering/biotechnology.

[10]  E. Lander,et al.  Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling , 2010, Proceedings of the National Academy of Sciences.

[11]  C. Eaves,et al.  Quantitation of human mammary epithelial stem cells with in vivo regenerative properties using a subrenal capsule xenotransplantation assay , 2010, Nature Protocols.

[12]  C. Clarke,et al.  Progesterone induces adult mammary stem cell expansion , 2010, Nature.

[13]  Michael D. Wilson,et al.  ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions. , 2009, Methods.

[14]  G. Turashvili,et al.  A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability , 2008, Nature Medicine.

[15]  Rebecca O Barnes,et al.  Influence of Evolution in Tumor Biobanking on the Interpretation of Translational Research , 2008, Cancer Epidemiology Biomarkers & Prevention.

[16]  Jun S. Song,et al.  Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity. , 2008, Cancer research.

[17]  Marco Marra,et al.  Transcriptome analysis of the normal human mammary cell commitment and differentiation process. , 2008, Cell stem cell.

[18]  C. Brisken,et al.  Stem Cells and the Stem Cell Niche in the Breast: An Integrated Hormonal and Developmental Perspective , 2007, Stem Cell Reviews.

[19]  B. Cullen,et al.  The imprinted H19 noncoding RNA is a primary microRNA precursor. , 2007, RNA.

[20]  L. Murphy,et al.  Estrogen Receptor-α Phosphorylated at Ser118 Is Present at the Promoters of Estrogen-Regulated Genes and Is Not Altered Due to HER-2 Overexpression , 2006 .

[21]  Clifford A. Meyer,et al.  Genome-wide analysis of estrogen receptor binding sites , 2006, Nature Genetics.

[22]  Igor Jurisica,et al.  The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. , 2006, Cancer research.

[23]  P. Chambon,et al.  Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Hilsenbeck,et al.  Hormones, receptors, and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancer , 2005, Breast Cancer Research.

[25]  D. Monté,et al.  H19 mRNA-like Noncoding RNA Promotes Breast Cancer Cell Proliferation through Positive Control by E2F1* , 2005, Journal of Biological Chemistry.

[26]  L. Murphy,et al.  Inducible upregulation of oestrogen receptor-beta1 affects oestrogen and tamoxifen responsiveness in MCF7 human breast cancer cells. , 2005, Journal of molecular endocrinology.

[27]  A. Howell,et al.  Steroid receptors in human breast cancer , 2004, Trends in Endocrinology & Metabolism.

[28]  K. Korach,et al.  Mammary Gland Development and Tumorigenesis in Estrogen Receptor Knockout Mice , 1997, Journal of Mammary Gland Biology and Neoplasia.

[29]  A. Howell,et al.  Estrogen Responsiveness and Control of Normal Human Breast Proliferation , 2004, Journal of Mammary Gland Biology and Neoplasia.

[30]  Sven Bilke,et al.  The gene expression response of breast cancer to growth regulators: patterns and correlation with tumor expression profiles. , 2003, Cancer research.

[31]  J. Ellenberg,et al.  Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. , 2003, Molecular cell.

[32]  T. Dupressoir,et al.  Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells. , 2002, Carcinogenesis.

[33]  L. Hornez,et al.  Cross-talk between mesenchyme and epithelium increases H19 gene expression during scattering and morphogenesis of epithelial cells. , 2002, Experimental cell research.

[34]  L. Murphy,et al.  Steroid receptors in human breast tumorigenesis and breast cancer progression. , 2002, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[35]  B. Katzenellenbogen,et al.  Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. , 2001, Journal of medicinal chemistry.

[36]  P. Goss,et al.  Estrogen and the risk of breast cancer. , 2001, The New England journal of medicine.

[37]  Myles Brown,et al.  Cofactor Dynamics and Sufficiency in Estrogen Receptor–Regulated Transcription , 2000, Cell.

[38]  B. Katzenellenbogen,et al.  Conformational Changes and Coactivator Recruitment by Novel Ligands for Estrogen Receptor-α and Estrogen Receptor-β: Correlations with Biological Character and Distinct Differences among SRC Coactivator Family Members. , 2000, Endocrinology.

[39]  James A. Clark,et al.  Induction of Mammary Gland Development in Estrogen Receptor-α Knockout Mice. , 2000, Endocrinology.

[40]  K. Korach,et al.  Induction of mammary gland development in estrogen receptor-alpha knockout mice. , 2000, Endocrinology.

[41]  S. Lottin,et al.  Steroid hormones modulate H19 gene expression in both mammary gland and uterus , 1999, Oncogene.

[42]  J. Sloane,et al.  Oestrogen receptor expression in the normal and pre‐cancerous breast , 1999, The Journal of pathology.

[43]  S. Lottin,et al.  H19 overexpression in breast adenocarcinoma stromal cells is associated with tumor values and steroid receptor status but independent of p53 and Ki-67 expression. , 1998, The American journal of pathology.

[44]  C. Eaves,et al.  Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast. , 1998, Differentiation; research in biological diversity.

[45]  A. Howell,et al.  Dissociation between steroid receptor expression and cell proliferation in the human breast. , 1997, Cancer research.

[46]  K. Korach,et al.  Estrogen receptor residues required for stereospecific ligand recognition and activation. , 1997, Molecular endocrinology.

[47]  V. Erdmann,et al.  The product of the imprinted H19 gene is an oncofetal RNA. , 1997, Molecular pathology : MP.

[48]  L. Skoog,et al.  Proliferation of breast epithelial cells in healthy women during the menstrual cycle. , 1997, American journal of obstetrics and gynecology.

[49]  P. Watson,et al.  The NCIC-Manitoba Breast Tumor Bank: a resource for applied cancer research. , 1996, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[50]  J. Coll,et al.  The H19 gene is expressed within both epithelial and stromal components of human invasive adenocarcinomas , 1995, Biology of the cell.

[51]  M. Rogers,et al.  Estrogen receptor expression of benign breast epithelium and its association with breast cancer. , 1994, Cancer research.

[52]  G. Riou,et al.  Expression of the human fetal bac h19 gene in invasive cancers. , 1993, International journal of oncology.

[53]  M. Tsai,et al.  Progesterone and estrogen , 1993 .

[54]  F Poirier,et al.  The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time of implantation in the developing embryo. , 1991, Development.

[55]  R. Shiu,et al.  Transcriptional regulation of c-myc oncogene expression by estrogen in hormone-responsive human breast cancer cells. , 1988, The Journal of biological chemistry.

[56]  C. Daniel,et al.  Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. , 1987, Cancer research.

[57]  H. Okayama,et al.  High-efficiency transformation of mammalian cells by plasmid DNA. , 1987, Molecular and cellular biology.

[58]  P. Chambon,et al.  Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[59]  S. Tilghman,et al.  Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[60]  W. McGuire.  Steroid receptors in human breast cancer. , 1978, Cancer research.

[61]  Richard Axel,et al.  Transfer of purified herpes virus thymidine kinase gene to cultured mouse cells , 1977, Cell.

[62]  C. Osborne,et al.  In vitro model systems for the study of hormone-dependent human breast cancer. , 1977, The New England journal of medicine.

[63]  P. Chambon,et al.  Activation of pS 2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7 ( nuclear run-on transcription / cycloheximide / steroid hormone / gene expression / induction ) , 2022 .