Abstract
Expression of estrogen and progesterone hormone receptors indicates a favorable prognosis due to the successful use of hormonal therapies such as tamoxifen and aromatase inhibitors. Unfortunately, 15–20% of patients will experience breast cancer recurrence despite continued use of tamoxifen. Drug resistance to hormonal therapies is of great clinical concern so it is imperative to identify novel molecular factors that contribute to tumorigenesis in hormone receptor positive cancers and/or mediate drug sensitivity. The hope is that targeted therapies, in combination with hormonal therapies, will improve survival and prevent recurrence. We have previously shown that the DEK oncogene, which is a chromatin remodeling protein, supports breast cancer cell proliferation, invasion and the maintenance of the breast cancer stem cell population. In this report, we demonstrate that DEK expression is associated with positive hormone receptor status in primary breast cancers and is up-regulated in vitro following exposure to the hormones estrogen, progesterone, and androgen. Chromatin immunoprecipitation experiments identify DEK as a novel estrogen receptor α (ERα) target gene whose expression promotes estrogen-induced proliferation. Finally, we report for the first time that DEK depletion enhances tamoxifen-induced cell death in ER+ breast cancer cell lines. Together, our data suggest that DEK promotes the pathogenesis of ER+ breast cancer and that the targeted inhibition of DEK may enhance the efficacy of conventional hormone therapies.
Highlights
Clinical and pathological characterization of breast cancer, the second leading cause of cancer-related deaths among women in the United States [1], is crucial for identifying the best course of treatment for each patient
Recent reports have shown that transcription of the DEK oncogene is up-regulated in breast cancers with strong gene expression detected in lymph node positive and late stage breast cancers, and that DEK expression correlated with increased recurrence rates after 3 years [3,4,5,6]
DEK is an Estrogen Receptor Target Gene In order to determine if DEK expression was associated with hormone receptor expression and activity in vitro, two ER+/PR+/ androgen receptor (AR)+ cell lines, MCF7 and T47D, and ER2/PR2/AR2 BT20 cells were cultured in hormone depleted charcoal-stripped serum (CS-FBS) treated with 10 nM 17b-estradiol (E2) to activate the estrogen receptor
Summary
Clinical and pathological characterization of breast cancer, the second leading cause of cancer-related deaths among women in the United States [1], is crucial for identifying the best course of treatment for each patient. There has been an increase in the percentage of breast cancers that are positive for the expression of ERa (‘‘ER+’’) such that nearly 75% of all breast cancers are ER+ [2]. Recent reports have shown that transcription of the DEK oncogene is up-regulated in breast cancers with strong gene expression detected in lymph node positive and late stage breast cancers, and that DEK expression correlated with increased recurrence rates after 3 years [3,4,5,6]. Work from our laboratory has shown that DEK protein levels are elevated in both cultured cell lines and primary invasive adenocarcinomas and that DEK expression stimulates breast cancer cell proliferation in vitro and in vivo, together with cellular invasion, and growth of the breast cancer stem cell population [7]
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