Top

Published in:

01-04-2011

Functional Significance of Aurora Kinase A Regulatory Interactions with p53–ERα Complex in Human Breast Cancer Cells

Authors: Hiroshi Katayama, Subrata Sen

Published in: Discover Oncology | Issue 2/2011

Abstract

Aurora kinase A (Aurora-A), a proto-oncogenic mitosis-regulating serine/threonine kinase, is frequently overexpressed in human breast cancer. While the kinase has been shown to cause functional inactivation of tumor suppressor protein p53, which binds estrogen receptor α (ERα) and downregulates its transcriptional activation function, significance of Aurora-A overexpression on p53 regulatory interactions in breast cancer cells has not been investigated. We describe in this report functional consequences of Aurora-A phosphorylation of p53 tumor suppressor protein on its subcellular distribution and binding with ERα that may be important in downregulating the transcription of p53-responsive growth inhibitory genes and development of resistance to DNA damage-induced apoptosis in Aurora-A overexpressing human breast cancer cells. Our results demonstrate that while estrogen activates Aurora-A expression in ERα-positive cells through ERα–GATA-3 signaling cascade, Aurora-A forms a ternary complex with p53 and ERα. Phosphorylation of p53 by Aurora-A sequesters the protein in the cytoplasm and enhances its interaction with ERα, thus repressing the transactivation functions of both p53 and ERα. These findings have significant clinical implications and suggest that prolonged estrogen exposure-mediated Aurora-A overexpression may be directly contributing to deregulated proliferation and resistance to DNA damage-induced apoptosis in breast cancer cells.

Marumoto T, Zhang D, Saya H (2005) Aurora-A—a guardian of poles. Nat Rev Cancer 5:42–50PubMedCrossRef

Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S (1998) Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193PubMedCrossRef

Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, Fiorica JV, Nicosia SV, Cheng JQ (2003) Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res 9:1420–1426PubMed

Hoque A, Carter J, Xia W, Hung MC, Sahin AA, Sen S, Lippman SM (2003) Loss of aurora A/STK15/BTAK overexpression correlates with transition of in situ to invasive ductal carcinoma of the breast. Cancer Epidemiol Biomark Prev 12:1518–1522

Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C et al (1998) A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17:3052–3065PubMedCrossRef

Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, Fujii S, Arlinghaus RB, Czerniak BA, Sen S (2004) Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 36:55–62PubMedCrossRef

Liu Q, Kaneko S, Yang L, Feldman RI, Nicosia SV, Chen J, Cheng JQ (2004) Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem 279:52175–52182PubMedCrossRef

Cattoretti G, Rilke F, Andreola S, D’Amato L, Delia D (1988) P53 expression in breast cancer. Int J Cancer 41:178–183PubMedCrossRef

Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET et al (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102:13550–13555PubMedCrossRef

10.

Olivier M, Langerød A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bièche I et al (2006) The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167PubMedCrossRef

11.

Liu W, Konduri SD, Bansal S, Nayak BK, Rajasekaran SA, Karuppayil SM, Rajasekaran AK, Das GM (2006) Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function. J Biol Chem 281:9837–9840PubMedCrossRef

12.

Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM (2007) Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res 67:7746–7755PubMedCrossRef

13.

Liu W, Ip MM, Podgorsak MB, Das GM (2009) Disruption of estrogen receptor alpha–p53 interaction in breast tumors: a novel mechanism underlying the anti-tumor effect of radiation therapy. Breast Cancer Res Treat 115:43–50PubMedCrossRef

14.

Jiang S, Katayama H, Wang J, Li SA, Hong Y, Radvanyi L, Li JJ, Sen S (2010) Estrogen-induced Aurora Kinase-A (AURKA) gene expression is activated by GATA-3 in estrogen receptor-positive breast cancer cells. Horm Cancer 1:11–20CrossRef

15.

Eeckhoute J, Keeton EK, Lupien M, Krum SA, Carroll JS, Brown M (2007) Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer. Cancer Res 67:6477–6483PubMedCrossRef

16.

Li JJ, Weroha SJ, Lingle WL, Papa D, Salisbury JL, Li SA (2004) Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats. Proc Natl Acad Sci US A101:18123–18128CrossRef

17.

Qin C, Nguyen T, Stewart J, Samudio I, Burghardt R, Safe S (2002) Estrogen up-regulation of p53 gene expression in MCF-7 breast cancer cells is mediated by calmodulin kinase IV-dependent activation of a nuclear factor kappaB/CCAAT-binding transcription factor-1 complex. Mol Endocrinol 16:1793–1809PubMedCrossRef

18.

Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y (1999) Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res 59:2041–2044PubMed

19.

Miyoshi Y, Iwao K, Egawa C, Noguchi S (2001) Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int J Cancer 92:370–373PubMedCrossRef

20.

Martin KJ, Patrick DR, Bissell MJ, Fournier MV (2008) Prognostic breast cancer signature identified from 3D culture model accurately predicts clinical outcome across independent datasets. PLoS ONE 3:e2994PubMedCrossRef

21.

Cox DG, Hankinson SE, Hunter DJ (2006) Polymorphisms of the AURKA (STK15/Aurora Kinase) gene and breast cancer risk (United States). Cancer Causes Control 17:81–83PubMedCrossRef

22.

Dai Q, Cai QY, Shu XO, Ewart-Toland A, Wen WQ, Balmain A, Gao YT, Zheng W (2004) Synergistic effects of STK15 gene polymorphisms and endogenous estrogen exposure in the risk of breast cancer. Cancer Epidemiol Biomark Prev 13:2065–2070

23.

Hurd C, Dinda S, Khattree N, Moudgil VK (1999) Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells. Oncogene 18:1067–1072PubMedCrossRef

24.

Sivaraman L, Conneely OM, Medina D, O’Malley BW (2001) p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. Proc Natl Acad Sci USA 98:12379–12384PubMedCrossRef

25.

Riley T, Sontag E, Chen P, Levine A (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9:402–412PubMedCrossRef

26.

Shirley SH, Rundhaug JE, Tian J, Cullinan-Ammann N, Lambertz I, Conti CJ, Fuchs-Young R (2009) Transcriptional regulation of estrogen receptor-alpha by p53 in human breast cancer cells. Cancer Res 69:3405–3414PubMedCrossRef

27.

Fuchs-Young R, Shirley SH, Lambertz I, Colby JK, Tian J, Johnston D, Gimenez-Conti IB, Donehower LA, Conti CJ, Hursting SD (2010) P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis. Breast Cancer Res Treat. doi:10.1007/s10549-010-1308-y PubMed

28.

Konduri SD, Medisetty R, Liu W, Kaipparettu BA, Srivastava P, Brauch H, Fritz P, Swetzig WM, Gardner AE, Khan SA et al (2010) Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc Natl Acad Sci USA 107:15081–15086PubMedCrossRef

29.

Varmus HE, Godley LA, Roy S, Taylor IC, Yuschenkoff L, Shi YP, Pinkel D, Gray J, Pyle R, Aldaz CM et al (1994) Defining the steps in a multistep mouse model for mammary carcinogenesis. Cold Spring Harb Symp Quant Biol 59:491–499PubMed

30.

Wang RA, Mazumdar A, Vadlamudi RK, Kumar R (2002) P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-α and promotes hyperplasia in mammary epithelium. EMBO J 21:5437–5447PubMedCrossRef

31.

Katayama H, Zhou H, Li Q, Tatsuka M, Sen S (2001) Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle. J Biol Chem 276:46219–46224PubMedCrossRef

32.

Katayama H, Sasai K, Kloc M, Brinkley BR, Sen S (2008) Aurora kinase-A regulates kinetochore/chromatin associated microtubule assembly in human cells. Cell Cycle 7:2691–2704PubMedCrossRef

Title: Functional Significance of Aurora Kinase A Regulatory Interactions with p53–ERα Complex in Human Breast Cancer Cells
Authors: Hiroshi Katayama
Subrata Sen
Publication date: 01-04-2011
Publisher: Springer-Verlag
Published in: Discover Oncology / Issue 2/2011
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-011-0070-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

Estrogen and Progesterone in Normal Mammary Gland Development and in Cancer

Letter from the Editor

Erratum to: Letter from the Editor

Targeting the Mitotic Checkpoint to Kill Tumor Cells

Expression and Relevance of TRPS-1: A New GATA Transcription Factor in Breast Cancer

Aberrant Activation of Cell Cycle Regulators, Centrosome Amplification, and Mitotic Defects

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials