title: Differential effects of estrogen-dependent transactivation vs. transrepression by the estrogen receptor on invasiveness of HER2 overexpressing breast cancer cells.
abstract: Estrogen (E2) supports breast cancer cell growth but suppresses invasiveness and both actions are antagonized by anti-estrogens. As a consequence, anti-estrogen treatment may increase the invasive potential of estrogen receptor (ER)+ tumor cell sub-populations that are endocrine resistant due to HER2 amplification. Either transactivation or transrepression by E2/ER could lead to both up- and down-regulation of many genes. Inhibition of the transactivation function of ER is adequate to inhibit E2-dependent growth. However, the impact of inhibiting E2-dependent transactivation vs. transrepression by ER on regulation of invasiveness by E2 is less clear. Here we dissect the roles of ER-mediated transactivation and transrepression in the regulation of invasiveness of ER+/HER2+ breast cancer cells by E2. Knocking down the general ER co-activators CBP and p300 prevented activation by E2 of its classical target genes but did not interfere with the ability of E2 to repress its direct target genes known to support invasiveness and tumor progression; there was also no effect on invasiveness or the ability of E2 to regulate invasiveness. On the other hand, overexpression of a co-repressor binding site mutant of ER (L372R) prevented E2-dependent transrepression but not transactivation. The mutant ER abrogated the ability of E2 to suppress invasiveness. E2 can partially down-regulate HER2 but knocking down HER2 below E2-regulated levels did not affect invasiveness or the ability of E2 to regulate invasiveness, although it did inhibit growth. Therefore, in ER+/HER2+ cells, the E2-dependent transrepression by ER rather than its transactivation function is critical for regulation of invasiveness and this is independent of HER2 regulation by E2. The findings suggest that selective inhibitors of transactivation by ER may be more beneficial in reducing tumor progression than conventional anti-estrogens that also antagonize E2-dependent transrepression.
authors.affiliation: Department of Oncology, Barbara Ann Karmanos Cancer Institute, 4100 John R., Detroit, MI 48201, USA; Department of Biochemistry and Cancer Biology, University Medical Center, Toledo, OH 43614, USA.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Patki
authors.affiliation: Department of Biochemistry and Cancer Biology, University Medical Center, Toledo, OH 43614, USA; Division of Translational Research, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Marcela d'alincourt
authors.initials: Md
authors.lastname: Salazar
authors.affiliation: Department of Biochemistry and Cancer Biology, University Medical Center, Toledo, OH 43614, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Trumbly
authors.affiliation: Department of Oncology, Barbara Ann Karmanos Cancer Institute, 4100 John R., Detroit, MI 48201, USA. Electronic address: ratnamm@karmanos.org.
authors.forename: Manohar
authors.initials: M
authors.lastname: Ratnam
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004958:Estradiol; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D004967:Estrogens; D018719:Erb-b2 Receptor Tyrosine Kinases; C506487:ESR1 protein, human; C508053:ERBB2 protein, human
keywords: Anti-estrogens; Breast cancer; Estrogen receptor; HER2; Invasiveness; Tamoxifen