title: New steroidal aromatase inhibitors: suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death.
abstract: BACKGROUND
  Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells.
  
  
  RESULTS
  The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death.
  
  
  CONCLUSIONS
  Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.
authors.affiliation: Biochemistry Laboratory, Faculty of Pharmacy, University of Oporto, Rua Aníbal Cunha, 164, 4099-030 Oporto, Portugal. margaridacepa@ff.up.pt
authors.forename: Margarida
authors.initials: M
authors.lastname: Cepa
authors.forename: Georgina
authors.initials: G
authors.lastname: Correia-da-Silva
authors.forename: Elisiário J Tavares
authors.initials: EJ
authors.lastname: da Silva
authors.forename: Fernanda M F
authors.initials: FM
authors.lastname: Roleira
authors.forename: Margarida
authors.initials: M
authors.lastname: Borges
authors.forename: Natércia A
authors.initials: NA
authors.lastname: Teixeira
mesh_terms: D015068:17-Ketosteroids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000731:Androstanes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004967:Estrogens; D005260:Female; D006801:Humans; D015394:Molecular Structure; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014617:Vacuoles / Q000648:ultrastructure
chemical_list: D015068:17-Ketosteroids; C505558:3,4-epoxy-5alpha-androstan-17-one; D000731:Androstanes; D047072:Aromatase Inhibitors; D004967:Estrogens; D011960:Receptors, Estrogen; D013256:Steroids; C531589:androst-3-en-17-one; D004247:DNA; D001141:Aromatase