Effect of bisphenol A exposure on mammary stem cell function and transformation

Summary

Principal Investigator: Luzhe Sun
Abstract: DESCRIPTION (provided by applicant): Exposure to environmental synthetic estrogens, such as bisphenol A (BPA), has been implicated to contribute to the increasing incidence of breast cancer. Bisphenol A is a most pervasive chemical in modern life as a component of polycarbonate plastics and epoxy resins used widely for food and beverage containers and dental sealants. Perinatal exposure to low, environmentally relevant doses of BPA in rodents resulted in induction of preneoplastic ductal hyperplasias, carcinoma in situ, and increased susceptibility to tumorigenesis. However, the underlying mechanism for these observations is unclear. The murine mammary stem cells (MaSCs) have the potential to drive mammary gland development during puberty, and growth and remodeling during pregnancy. Recent lineage tracing studies also indicated the presence of a hierarchy of stem cells in the murine mammary gland. Significantly, these distinct unipotent basal and luminal MaSCs have been matched with different subtypes of breast cancer by their specific gene-expression signatures. Furthermore, modulation of oncogenes and tumor suppressors has been shown to increase stem cell compartment and self-renewal function of MaSCs, suggesting that alteration of MaSC frequency and function may lead to transformation and tumorigenesis. Unpublished results indicate that low dose BPA exposure during puberty can alter the number of different lineage MaSCs. Recent animal studies showed that BPA also promoted tumor cell growth through estrogenic signaling implicating the risk of development and progression of mammary cancer by BPA exposure at various time points throughout the lifespan. Thus it is hypothesized that mammary gland exposed to BPA at a susceptible window may lead to its susceptibility to tumorigenesis through a MaSC and/or stem cell niche mediated mechanism. In addition to mice, the intent is to also use common marmoset to determine the effect of BPA on its MaSC function and transformation because nonhuman primates, with their close phylogenetic relationship to humans, can better simulate the effects of physiological and pathological factors on humans. This hypothesis will be tested with three specific aims. First, the effect of BPA will be determined on MaSC function of non-primate and primate subjects. A novel in vitro assay developed in this laboratory will be exploited, instead of cell surface markers that are not specific for MaSCs, to quantify the alteration of basal and luminal MaSC number after systemic BPA treatment in various developmental windows of the mammary gland of mice and marmoset. Second, a determination of the effect of low dose irradiation on the transformation potential of MaSCs derived from BPA-exposed mice will be accomplished. The hypothesis to be tested for this specific aim is that the transforming activity of BPA may be more evident in combination with a DNA damaging agent such as ionizing radiation, which is a known risk factor for breast cancer. Third, the effect of BPA treatment on MaSC function of obese mice and marmosets will be examined. This proposed research will not only answer the question of whether BPA- induced morphogenesis changes in different developmental windows of mammary gland has a stem cell origin, but also shed light on MaSC susceptibility to multiple risk factor-induced cell transformation such as xenoestrogens, irradiation, and obesity, which will have important implications in disease prevention for human breast cancer.
Funding Period: 2012-08-23 - 2017-04-30
more information: NIH RePORT

Top Publications

  1. pmc Mammospheres from murine mammary stem cell-enriched basal cells: clonal characteristics and repopulating potential
    Qiaoxiang Dong
    Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78299, USA
    Stem Cell Res 10:396-404. 2013
  2. pmc Pubertal bisphenol A exposure alters murine mammary stem cell function leading to early neoplasia in regenerated glands
    Danhan Wang
    University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229 and L Z Sun
    Cancer Prev Res (Phila) 7:445-55. 2014

Detail Information

Publications2

  1. pmc Mammospheres from murine mammary stem cell-enriched basal cells: clonal characteristics and repopulating potential
    Qiaoxiang Dong
    Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78299, USA
    Stem Cell Res 10:396-404. 2013
    ..Thus, this in vitro sphere formation and differentiation assay is a reliable alternative to the in vivo repopulation assay for the study of MaSCs...
  2. pmc Pubertal bisphenol A exposure alters murine mammary stem cell function leading to early neoplasia in regenerated glands
    Danhan Wang
    University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229 and L Z Sun
    Cancer Prev Res (Phila) 7:445-55. 2014
    ..Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation...

Research Grants30

  1. Eliciting B cells to produce anti-HIV gp41 MPER-specific neutralizing antibodies
    Ellis L Reinherz; Fiscal Year: 2013
    ..In conjunction with Projects 1- 3, kinetics of memory B cell and long-lived plasma cell populations will be ascertained and optimized. An Administrative Core with a Partnership Plan is included. ..
  2. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  3. Molecular Pathogenesis of Basal-like Breast Cancer
    Richard J Baer; Fiscal Year: 2013
    ..e., metastasis, and develop strategies for therapy. ..
  4. SPORE in Soft Tissue Sarcoma
    Samuel Singer; Fiscal Year: 2013
    ..abstract_text> ..
  5. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  6. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  7. Molecular and Clinical Approaches to Colon Cancer Precursors
    SEAN VAHRAM TAVTIGIAN; Fiscal Year: 2013
    ..abstract_text> ..
  8. Genetic Regulatory Network in Mammary Gland Development and Tumorigenesis
    Wei Hsu; Fiscal Year: 2013
    ..abstract_text> ..
  9. INTEGRATIVE PATHOPHYSIOLOGY OF SOLID TUMORS
    Rakesh K Jain; Fiscal Year: 2013
    ..abstract_text> ..
  10. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....
  11. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  12. Mechanism of developmental toxicity of Bisphenol-A
    ANA SOTO; Fiscal Year: 2013
    ..3: that the different mammary gland phenotypes resulting from gestational and gestational plus lactational BPA exposure are due to alterations at the hypothalamic level. ..
  13. BPA as a Developmental Carcinogen
    ANA SOTO; Fiscal Year: 2013
    ..This knowledge is crucial for the toxicological evaluation of BPA. The success of this project would suggest the addition of some of these mammary gland end points to the toxicological assessment of chemicals. ..
  14. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  15. Neurobehavioral effects of Bisphenol A Across age and sex
    CHERYL SUSAN ROSENFELD; Fiscal Year: 2013
    ..These studies will provide critical observational and mechanistic insights into whether or not early exposure to BPA increases the risk for behavioral abnormalities in a sex-specific manner in children. ..