-
Yuting Sun,
Bu-Er Wang,
Kevin G Leong,
Peng Yue,
Li Li, Suchit Jhunjhunwala,
Darrell Chen,
Kyounghee Seo,
Zora Modrusan,
Wei-Qiang Gao,
Jeffrey Settleman,
Leisa Johnson
[show abstract]
[hide abstract]
ABSTRACT: Androgen deprivation is currently a standard-of-care, first-line therapy for prostate cancer in the United States. Although this regimen effectively regresses androgen-dependent disease, relapse often occurs in an androgen-independent manner and is associated with poor prognosis. Such castration-resistant prostate cancer represents a major clinical challenge, and the mechanisms underlying castration resistance are not fully understood. Epithelial-mesenchymal transition (EMT) is a key developmental process and has also been implicated in cancer metastasis and therapeutic resistance in recent years. However, the factors contributing to EMT in human cancers remain unclear. Here, we show that both normal mouse prostate tissue and human LuCaP35 prostate tumor explants display an EMT as well as increased stem cell-like features following androgen deprivation. Importantly, we observed similar changes in mesenchymal features in prostate tumors from patients treated with androgen-deprivation therapy. In addition, we have delineated a feedback loop involving the androgen receptor and the Zeb1 transcription factor that seems to mediate this transition. In summary, we show for the first time that androgen deprivation induces EMT in both normal prostate and prostate cancer, revealing a potentially important consequence of a standard-of-care treatment for prostate cancer. This finding could have significant implications for second-line treatment strategies in this clinical setting.
Cancer Research 11/2011; 72(2):527-36. · 7.86 Impact Factor
-
Susanna Stinson,
Mark R Lackner,
Alex T Adai,
Nancy Yu,
Hyo-Jin Kim,
Carol O'Brien,
Jill Spoerke, Suchit Jhunjhunwala,
Zachary Boyd,
Thomas Januario,
Robert J Newman,
Peng Yue,
Richard Bourgon,
Zora Modrusan,
Howard M Stern,
Søren Warming,
Frederic J de Sauvage,
Lukas Amler,
Ru-Fang Yeh,
David Dornan
[show abstract]
[hide abstract]
ABSTRACT: Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expression of epithelial-specific genes and increase expression of mesenchymal-specific genes. In addition, expression of these miRNAs increased cell migration and invasion, which collectively are characteristics of the epithelial-to-mesenchymal transition (EMT). The basal-like transcription factor FOSL1 (also known as Fra-1) directly stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. The miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting of the 3' untranslated region (3'UTR) of TRPS1 (trichorhinophalangeal syndrome type 1), which is a member of the GATA family of transcriptional repressors. TRPS1 inhibited EMT by directly repressing expression of ZEB2 (Zinc finger E-box-binding homeobox 2). Therefore, miR-221/222 may contribute to the aggressive clinical behavior of basal-like breast cancers.
Science Signaling 08/2011; 4(186):pt5. · 7.50 Impact Factor
-
Susanna Stinson,
Mark R Lackner,
Alex T Adai,
Nancy Yu,
Hyo-Jin Kim,
Carol O'Brien,
Jill Spoerke, Suchit Jhunjhunwala,
Zachary Boyd,
Thomas Januario,
Robert J Newman,
Peng Yue,
Richard Bourgon,
Zora Modrusan,
Howard M Stern,
Søren Warming,
Frederic J de Sauvage,
Lukas Amler,
Ru-Fang Yeh,
David Dornan
[show abstract]
[hide abstract]
ABSTRACT: The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to-mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra-1), which is found in basal-like breast cancers but not in the luminal subtype, stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. Furthermore, miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting the 3' untranslated region of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1), which inhibited EMT by decreasing ZEB2 (zinc finger E-box-binding homeobox2) expression. We conclude that by promoting EMT, miR-221/222 may contribute to the more aggressive clinical behavior of basal-like breast cancers.
Science Signaling 01/2011; 4(177):ra41. · 7.50 Impact Factor
