title: Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes.
abstract: Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b-mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.
authors.affiliation: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Augello
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Burd
authors.forename: Ruth
authors.initials: R
authors.lastname: Birbe
authors.forename: Christopher
authors.initials: C
authors.lastname: McNair
authors.forename: Adam
authors.initials: A
authors.lastname: Ertel
authors.forename: Michael S
authors.initials: MS
authors.lastname: Magee
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Frigo
authors.forename: Kari
authors.initials: K
authors.lastname: Wilder-Romans
authors.forename: Mark
authors.initials: M
authors.lastname: Shilkrut
authors.forename: Sumin
authors.initials: S
authors.lastname: Han
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Jernigan
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatatis
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: C530104:CCND1 protein, human; D011944:Receptors, Androgen; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D019938:Cyclin D1