title: A mechanistic study of the effect of doxorubicin/adriamycin on the estrogen response in a breast cancer model.
abstract: OBJECTIVE
  Estrogen treatment limits the cytotoxic effects of chemotherapy in estrogen receptor-positive (ER+) breast cancer cell lines, suggesting that estrogen pathway signaling may confer chemotherapeutic resistance. This study investigates the molecular responses of ER+ breast cancer cell lines to the chemotherapeutic agent, doxorubicin, in the presence or absence of estrogen.
  
  
  METHODS
  ER+ MCF-7 and T47-D cells were cultured in hormone-starved or estrogen-containing media with or without doxorubicin at concentrations mimicking the low concentrations seen in plasma and tumor microenvironments in humans following typical bolus administration. Protein levels, phosphorylations, and interactions of estrogen-signaling molecules were assessed following these treatments, as well the effects of ER signaling inhibitors on cell proliferation.
  
  
  RESULTS
  Surprisingly, estrogen and doxorubicin co-treatment markedly induced pro-growth alterations compared to doxorubicin alone and modestly enhanced estrogen alone-induced changes. Several inhibitors suppressed cell proliferation in the presence of doxorubicin and estrogen.
  
  
  CONCLUSIONS
  These findings demonstrate that molecular changes caused by doxorubicin in ER+ breast cancer cells can be reversed by estrogen, providing molecular evidence for the poorer responses of ER+ tumors to doxorubicin in the presence of physiologic estrogen levels. Our results also suggest that the addition of drugs targeting the ER, EGFR, the SFKs, MEK, PI3K, and/or the MMP proteins to a conventional chemotherapy regimen may improve chemosensitivity.
authors.affiliation: Department of Microbiology and Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Pritchard
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dillon
authors.forename: Mark R
authors.initials: MR
authors.lastname: Conaway
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Silva
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parsons
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D004958:Estradiol; D004317:Doxorubicin