title: Regulating the tumor suppressor gene maspin in breast cancer cells: a potential mechanism for the anticancer properties of tamoxifen.
abstract: OBJECTIVE
  Mammary epithelial cells and the majority of breast cancer tumors require estrogen for continued growth. Antiestrogen therapy alone, or in combination with other drugs, has long been a common procedure for breast cancer treatment and prophylaxis. Thus, there is a critical need to elucidate the mechanism(s) of action of antiestrogen treatment, especially for patients who are at risk of breast cancer development or who are currently receiving hormone therapy. In this study, we examined the ability of hormones to regulate the expression of a tumor suppressor gene, maspin, which is a serine protease inhibitor (serpin) that plays an important role in mammary gland development and is silenced during breast cancer progression. Specifically, our hypothesis tested the clinical efficacy of tamoxifen to regulate maspin expression.
  
  
  METHODS
  We used maspin promoter luciferase reporter plasmids that were transfected into normal human mammary epithelial (HMEC1331) and MCF-7 breast cancer cells, followed by determination of the effect of hormones and their antagonists on maspin promoter activity. At the protein level, cytosolic fractions from both cell types before and after hormone treatment were subjected to Western blot analysis to determine maspin level.
  
  
  CONCLUSIONS
  Our studies revealed that the antiestrogen tamoxifen induces maspin promoter activity. Interestingly, antiandrogen flutamide could also induce maspin in both cell lines tested. These observations were further confirmed in patient tissues. These novel findings provide a new mechanism of action for tamoxifen under normal and pathological conditions. More significantly, these findings could have a potential impact on future therapeutic intervention strategies for breast cancer.
authors.affiliation: Department of Anatomy and Cell Biology and the Holden Comprehensive Cancer Center at The University of Iowa, Iowa City, Iowa 52242-1109, USA. zhila-ellis@uiowa.edu
authors.forename: Zhila
authors.initials: Z
authors.lastname: Khalkhali-Ellis
authors.forename: Abby L
authors.initials: AL
authors.lastname: Christian
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Kirschmann
authors.forename: Elijah M
authors.initials: EM
authors.lastname: Edwards
authors.forename: Maryam
authors.initials: M
authors.lastname: Rezaie-Thompson
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Vasef
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Gruman
authors.forename: Richard E B
authors.initials: RE
authors.lastname: Seftor
authors.forename: Laura E
authors.initials: LE
authors.lastname: Norwood
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005485:Flutamide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008875:Middle Aged; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins; D015843:Serpins / Q000096:biosynthesis*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000199:Actins; D018931:Antineoplastic Agents, Hormonal; D006728:Hormones; D011506:Proteins; C085344:SERPIN-B5; D015843:Serpins; D013629:Tamoxifen; D005485:Flutamide; D008156:Luciferases