Abstract
Triple negative breast cancer (TNBC), which comprises approximately 15% of all primary breast cancer diagnoses, lacks estrogen receptor alpha, progesterone receptor and human epidermal growth factor receptor 2 expression. However, we, and others, have demonstrated that approximately 30% of TNBCs express estrogen receptor beta (ERβ), a nuclear hormone receptor and potential drug target. Treatment of ERβ expressing MDA-MB-231 cells with estrogen or the ERβ selective agonist, LY500307, was shown to result in suppression of cell proliferation. This inhibitory effect was due to blockade of cell cycle progression. In vivo, estrogen treatment significantly repressed the growth of ERβ expressing MDA-MB-231 cell line xenografts. Gene expression studies and ingenuity pathway analysis identified a network of ERβ down-regulated genes involved in cell cycle progression including CDK1, cyclin B and cyclin H. siRNA mediated knockdown or drug inhibition of CDK1 and CDK7 in TNBC cells resulted in substantial decreases in proliferation regardless of ERβ expression. These data suggest that the tumor suppressive effects of ERβ in TNBC result from inhibition of cell cycle progression, effects that are in part mediated by suppression of CDK1/7. Furthermore, these data indicate that blockade of CDK1/7 activity in TNBC may be of therapeutic benefit, an area of study that has yet to be explored.
Highlights
Triple negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers diagnosed [1, 2] and is defined by the absence of estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification [1, 2]
Ligand-mediated activation of estrogen receptor beta (ERβ) results in the suppression of a network of genes involved in cell cycle progression including CDK1, CDK7, cyclin B and cyclin H. siRNA-mediated depletion, or drug inhibition of CDK1 and CDK7 resulted in substantial decreases in TNBC cell proliferation, effects that were independent of ERβ expression
Using a doxycycline (Dox)-inducible ERβ expressing MDA-MB-231 cell line generated in our laboratory, we have confirmed that ligand mediated transcriptional activation of ERβ with www.impactjournals.com/oncotarget either estrogen or multiple doses of the highly selective ERβ agonist, LY500307, (Figure 1A) results in significant inhibition of TNBC cell proliferation following five days of treatment (Figure 1B)
Summary
Triple negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers diagnosed [1, 2] and is defined by the absence of estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification [1, 2]. TNBC typically occurs in young, pre-menopausal women and is more prevalent in women of African-American decent [3]. Women diagnosed with TNBC usually present with larger tumors of higher grade that have spread to the lymph nodes [4]. Despite current treatment strategies which include surgery, chemotherapy, and radiation therapy, patients with TN disease are faced with a poor prognosis [5]. 34% of patients with newly diagnosed TNBC will develop recurrent disease within five years of diagnosis following aggressive chemotherapy treatment [5]. A better understanding of the molecular pathways responsible for driving TNBC development and progression, and the concurrent identification of novel therapeutic drug targets, are vital steps to combatting this breast cancer subtype
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