Leupaxin is expressed in mammary carcinoma and acts as a transcriptional activator of the estrogen receptor α

Kaulfuss,Silke; Herr,Anna-Maria; Büchner,Anja; Hemmerlein,Bernhard; Günthert,Andreas  R.; Burfeind,Peter

doi:10.3892/ijo.2015.2988

Leupaxin is expressed in mammary carcinoma and acts as a transcriptional activator of the estrogen receptor α

Authors:
- Silke Kaulfuss
- Anna-Maria Herr
- Anja Büchner
- Bernhard Hemmerlein
- Andreas R. Günthert
- Peter Burfeind
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Affiliations: Institute of Human Genetics, University Medical Center Göttingen, Germany, Department of Pathology, University Medical Center Göttingen, Germany, Department of Gynaecology and Obstetrics, University Medical Center Göttingen, Germany
Published online on: May 6, 2015 https://doi.org/10.3892/ijo.2015.2988
Pages: 106-114
Copyright: © Kaulfuss et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Leupaxin belongs to the group of paxillin proteins and was reported to play a major role in the invasion and migration of prostate cancer cells. In the present study we were able to show by using a cDNA cancer profiling array that leupaxin is upregulated in breast and endometrial cancer, whereas downregulation of leupaxin was observed in lung cancer. In addition, immunohistochemical studies using a leupaxin-specific antibody on human breast cancer specimens (n=127) revealed that leupaxin is expressed mainly in invasive ductal carcinomas and ductal carcinoma in situ (40 and 49% respectively), and only in a minority of lobular mammary carcinomas. To further investigate the role of leupaxin in the progression of breast cancer the expression of leupaxin was analysed in six breast cancer cell lines. The estrogen receptor α (ERα)-positive HCC70 and the ERα-negative MDA-MB‑231 cells showed leupaxin expression on the RNA and protein level. Leupaxin localizes in these mammary carcinoma cells at focal adhesion sites and shuttles between membrane and nucleus via its LD4 motif as major nuclear export signal. Interaction partners of leupaxin in the nucleus represent the estrogen receptors ERα and ERβ. Both ERα and ERβ bind to the LIM domains of leupaxin via their AF-1/DNA binding domains. Furthermore, leupaxin is able to induce transcriptional activity of ERα independent of the presence of estradiol. The specific downregulation of leupaxin expression using siRNAs in mammary carcinoma cells resulted in reduced migratory capability and diminished invasiveness whereas no effect on proliferation was observed. Collectively, these results show that leupaxin has particular influence on the progression and invasion of breast cancer cells and may therefore represent an interesting candidate protein for diagnosis and therapeutic interventions.

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1	Carlson RW, Anderson BO, Burstein HJ, Carter WB, Edge SB, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF, Hudis CA, et al: Invasive breast cancer. J Natl Compr Canc Netw. 5:246–312. 2007.PubMed/NCBI
2	Cufer T: Reducing the risk of late recurrence in hormone-responsive breast cancer. Ann Oncol. 18(Suppl 8): viii18–viii25. 2007. View Article : Google Scholar : PubMed/NCBI
3	Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK and Buzdar AU: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol. 14:2197–2205. 1996.PubMed/NCBI
4	Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A, Treuter E, Warner M, et al: Estrogen receptors: How do they signal and what are their targets. Physiol Rev. 87:905–931. 2007. View Article : Google Scholar : PubMed/NCBI
5	Roger P, Sahla ME, Mäkelä S, Gustafsson JA, Baldet P and Rochefort H: Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Res. 61:2537–2541. 2001.PubMed/NCBI
6	Zhao M and Ramaswamy B: Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol. 5:248–262. 2014. View Article : Google Scholar : PubMed/NCBI
7	Ali S and Coombes RC: Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2:101–112. 2002. View Article : Google Scholar
8	Musgrove EA and Sutherland RL: Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 9:631–643. 2009. View Article : Google Scholar : PubMed/NCBI
9	Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM and Schiff R: Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst. 95:353–361. 2003. View Article : Google Scholar : PubMed/NCBI
10	Kasai M, Guerrero-Santoro J, Friedman R, Leman ES, Getzenberg RH and DeFranco DB: The Group 3 LIM domain protein paxillin potentiates androgen receptor transactivation in prostate cancer cell lines. Cancer Res. 63:4927–4935. 2003.PubMed/NCBI
11	Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A and Chang C: Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem. 274:8316–8321. 1999. View Article : Google Scholar : PubMed/NCBI
12	Sundberg-Smith LJ, DiMichele LA, Sayers RL, Mack CP and Taylor JM: The LIM protein leupaxin is enriched in smooth muscle and functions as an serum response factor cofactor to induce smooth muscle cell gene transcription. Circ Res. 102:1502–1511. 2008. View Article : Google Scholar : PubMed/NCBI
13	Kaulfuss S, Grzmil M, Hemmerlein B, Thelen P, Schweyer S, Neesen J, Bubendorf L, Glass AG, Jarry H, Auber B, et al: Leupaxin, a novel coactivator of the androgen receptor, is expressed in prostate cancer and plays a role in adhesion and invasion of prostate carcinoma cells. Mol Endocrinol. 22:1606–1621. 2008. View Article : Google Scholar : PubMed/NCBI
14	Grzmil M, Kaulfuss S, Thelen P, Hemmerlein B, Schweyer S, Obenauer S, Kang TW and Burfeind P: Expression and functional analysis of Bax inhibitor-1 in human breast cancer cells. J Pathol. 208:340–349. 2006. View Article : Google Scholar
15	Grzmil M, Thelen P, Hemmerlein B, Schweyer S, Voigt S, Mury D and Burfeind P: Bax inhibitor-1 is overexpressed in prostate cancer and its specific down-regulation by RNA interference leads to cell death in human prostate carcinoma cells. Am J Pathol. 163:543–552. 2003. View Article : Google Scholar : PubMed/NCBI
16	Renoir JM, Marsaud V and Lazennec G: Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol. 85:449–465. 2013. View Article : Google Scholar
17	Panousis D, Patsouris E, Lagoudianakis E, Pappas A, Kyriakidou V, Voulgaris Z, Xepapadakis G, Manouras A, Athanassiadou AM and Athanassiadou P: The value of TOP2A, EZH2 and paxillin expression as markers of aggressive breast cancer: Relationship with other prognostic factors. Eur J Gynaecol Oncol. 32:156–159. 2011.PubMed/NCBI
18	Short SM, Yoder BJ, Tarr SM, Prescott NL, Laniauskas S, Coleman KA, Downs-Kelly E, Pettay JD, Choueiri TK, Crowe JP, et al: The expression of the cytoskeletal focal adhesion protein paxillin in breast cancer correlates with HER2 overexpression and may help predict response to chemotherapy: A retrospective immunohistochemical study. Breast J. 13:130–139. 2007. View Article : Google Scholar : PubMed/NCBI
19	Deakin NO and Turner CE: Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis. Mol Biol Cell. 22:327–341. 2011. View Article : Google Scholar :
20	Shibanuma M, Kim-Kaneyama JR, Ishino K, Sakamoto N, Hishiki T, Yamaguchi K, Mori K, Mashimo J and Nose K: Hic-5 communicates between focal adhesions and the nucleus through oxidant-sensitive nuclear export signal. Mol Biol Cell. 14:1158–1171. 2003. View Article : Google Scholar : PubMed/NCBI
21	Dong JM, Lau LS, Ng YW, Lim L and Manser E: Paxillin nuclear-cytoplasmic localization is regulated by phosphorylation of the LD4 motif: Evidence that nuclear paxillin promotes cell proliferation. Biochem J. 418:173–184. 2009. View Article : Google Scholar