DREAM, a possible answer to the estrogen paradox of the Women's Health Initiative Trial

Abstract

Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women's Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30 core ) and post-treatment (PRESTO-45 surg ) gene expression profiles. The PRESTO-30 core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45 surg , thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show estrogen modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

DREAM On, DREAM Off: A Review of the Estrogen Paradox in Luminal A Breast Cancers

“…We used a Window of Opportunity Study (PRESTO–PRe-operative ESTradiOl Window of Opportunity Study in Post-Menopausal Women with Newly Diagnosed ER Positive Breast Cancer) to test the hypothesis that estrogen could induce a decrease in Ki67 or Risk of Recurrence Score (ROR) (BC360™, NanoString Technologies Inc., Seattle, WA, USA) [ 27 ]. Nineteen women with newly diagnosed ER+, low-grade breast cancer who were post-menopausal with at least 5 years from their last estrogen exposure were given 6mg/day of estradiol [ 28 ] for 7 to 14 days in the interval between diagnosis and surgery.…”

“…There is activation of the DREAM pathway with the downregulation (green) of DREAM-regulated genes with single-hormone administration in vitro of DHT in ER+ PDX HCI-005 and GAR15-13 [ 65 ] or estrogens (ER10, ER-transfected MCF-7 cells [ 21 ]), as well as ER+ breast cancers in post-menopausal patients who respond with a post-treatment decrease in ROR to estrogen (PRESTO-R [ 27 ]), aromatase inhibitors (POETIC-R [ 73 ]) or ICI 182,780 (NEWEST-R [ 77 ]). Patients who have not responded with a decrease in ROR score to either ICI 182,780 (NEWEST non-R [ 77 ]), aromatase inhibitors (POETIC non-R [ 73 ]) or estrogen (PRESTO non-R [ 27 ]) show minimal change in these genes. Even though the ZR-75-1 cell line expresses the AR and is growth-inhibited by DHT, there are no changes in DREAM genes with DHT [ 65 ].…”

Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches

“…A window of opportunity PRe-operative ESTradiOl (PRESTO) trial was conducted, enrolling 19 postmenopausal breast cancer patients with early disease and treated with 6 mg E2 daily for 12 days (Table 1) [33]. Two gene signatures were developed: a pretreatment or predictive gene signature derived from biopsy cores (PRESTO-30 core ) and a post-treatment signature at the time of surgery (PRESTO-45 surg ).…”