Top

Published in:

01-06-2012 | Preclinical Study

Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer

Authors: Juan P. Cerliani, Silvia I. Vanzulli, Cecilia Pérez Piñero, María C. Bottino, Ana Sahores, Myriam Nuñez, Romina Varchetta, Rubén Martins, Eduardo Zeitlin, Stephen M. Hewitt, Alfredo A. Molinolo, Claudia Lanari, Caroline A. Lamb

Published in: Breast Cancer Research and Treatment | Issue 3/2012

Abstract

Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-β-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.

Available only for authorised users

Morrison RS, Yamaguchi F, Bruner JM et al (1994) Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme. Cancer Res 54:2794–2799PubMed

Yoshimura N, Sano H, Hashiramoto A et al (1998) The expression and localization of fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1) in human breast cancer. Clin Immunol Immunopathol 89:28–34PubMedCrossRef

Giri D, Ropiquet F, Ittmann M (1999) Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 5:1063–1071PubMed

Ahmed NU, Ueda M, Ito AM et al (1997) Expression of fibroblast growth factor receptors in naevus-cell naevus and malignant melanoma. Melanoma Res 7:299–305PubMedCrossRef

Myoken Y, Myoken Y, Okamoto T et al (1996) Expression of fibroblast growth factor-1 (FGF-1), FGF-2 and FGF receptor-1 in a human salivary-gland adenocarcinoma cell line: evidence of growth. Int J Cancer 65:650–657PubMedCrossRef

Shingu K, Fujimori M, Ito K et al (1998) Expression of fibroblast growth factor-2 and fibroblast growth factor receptor-1 in thyroid diseases: difference between neoplasms and hyperplastic lesions. Endocr J 45:35–43PubMedCrossRef

Bernard RS, Zheng L, Liu W et al (2005) Fibroblast growth factor receptors as molecular targets in thyroid carcinoma. Endocrinology 146:1145–1153CrossRef

Powers CJ, McLeskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7:165–197PubMedCrossRef

Hynes NE, Dey JH (2010) Potential for targeting the fibroblast growth factor receptors in breast cancer. Cancer Res 70:5199–5202PubMedCrossRef

10.

Giulianelli S, Cerliani JP, Lamb CA et al (2008) Carcinoma-associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: A role for the FGF-2/FGFR-2 axis. Int J Cancer 123:2518–2531PubMedCrossRef

11.

Cerliani JP, Guillardoy T, Giulianelli S et al (2011) Interaction between FGFR-2, STAT5, and progesterone receptors in breast cancer. Cancer Res 71:3720–3731PubMedCrossRef

12.

Imagawa W, Pedchenko VK, Helber J et al (2000) Attenuation and loss of hormonal modulation of KGF (FGF-7)/KGF receptor expression and mitogenesis during mammary tumor progression. J Cell Physiol 184:222–228PubMedCrossRef

13.

Ishii K, Imamura T, Iguchi K et al (2009) Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo. Endocr Relat Cancer 16:415–428PubMedCrossRef

14.

Chodosh LA, Gardner HP, Rajan JV et al (2000) Protein kinase expression during murine mammary development. Dev Biol 219:259–276PubMedCrossRef

15.

Shiang CY, Qi Y, Wang B et al (2010) Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate. Breast Cancer Res Treat 123:747–755PubMedCrossRef

16.

Turner N, Pearson A, Sharpe R et al (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70:2085–2094PubMedCrossRef

17.

Institute of Laboratory Animal Resources CoLSNRC (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington, DC

18.

Lanari C, Lamb CA, Fabris VT et al (2009) The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer. Endocr Relat Cancer 16:333–350PubMedCrossRef

19.

Bloom HJG, Richardson WW (1957) Histological grading and prognosis in breast cancer. Br J Cancer 11:359–377PubMedCrossRef

20.

Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410PubMedCrossRef

21.

Vanzulli SI, Soldati R, Meiss R et al (2005) Estrogen or antiprogestin treatment induces complete regression of pulmonary and axillary metastases in an experimental model of breast cancer progression. Carcinogenesis 26:1055–1063PubMedCrossRef

22.

Molinolo AA, Hewitt SM, Amornphimoltham P et al (2007) Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res 13:4964–4973PubMedCrossRef

23.

Helguero LA, Viegas M, Asaithamby A et al (2003) Progesterone receptor expression in medroxyprogesterone acetate-induced murine mammary carcinomas and response to endocrine treatment. Breast Cancer Res Treat 79:379–390PubMedCrossRef

24.

Brisken C, O’Malley B (2010) Hormone action in the mammary gland. Cold Spring Harb Perspect Biol 2:a003178PubMedCrossRef

25.

Montero GG, Vanzulli SI, Cerliani JP et al (2007) Association of estrogen receptor alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. Breast Cancer Res 9:R22CrossRef

26.

Pandit SG, Govindraj P, Sasse J et al (2002) The fibroblast growth factor receptor, FGFR3, forms gradients of intact and degraded protein across the growth plate of developing bovine ribs. Biochem J 361:231–241PubMedCrossRef

27.

Zhu X, Asa SL, Ezzat S (2009) Histone-acetylated control of fibroblast growth factor receptor 2 intron 2 polymorphisms and isoform splicing in breast cancer. Mol Endocrinol 23:1397–1405PubMedCrossRef

28.

Hollestelle A, Nagel JH, Smid M et al (2010) Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat 121:53–64PubMedCrossRef

29.

Bruzzone A, Vanzulli SI, Soldati R et al (2009) Novel human breast cancer cell lines IBH-4, IBH-6, and IBH-7 growing in nude mice. J Cell Physiol 219:477–484PubMedCrossRef

30.

Lu P, Ewald AJ, Martin GR et al (2008) Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis. Dev Biol 321:77–87PubMedCrossRef

31.

Parsa S, Ramasamy SK, De Langhe S et al (2008) Terminal end bud maintenance in mammary gland is dependent upon FGFR2b signaling. Dev Biol 317:121–131PubMedCrossRef

32.

Pond AC, Herschkowitz JI, Schwertfeger KL et al (2010) Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer. Cancer Res 70:4868–4879PubMedCrossRef

33.

Johnston CL, Cox HC, Gomm JJ et al (1995) Fibroblast growth factor receptors (FGFRs) localize in different cellular compartments. A splice variant of FGFR-3 localizes to the nucleus. J Biol Chem 270:30643–30650PubMedCrossRef

34.

Tannheimer SL, Rehemtulla A, Ethier SP (2000) Characterization of fibroblast growth factor receptor 2 overexpression in the human breast cancer cell line SUM-52PE. Breast Cancer Res 2:311–320PubMedCrossRef

35.

Luqmani YA, Graham M, Coombes RC (1992) Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues. Br J Cancer 66:273–280PubMedCrossRef

36.

Turner N, Lambros MB, Horlings HM et al (2010) Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 29:2013–2023PubMedCrossRef

37.

Fillmore CM, Gupta PB, Rudnick JA et al (2010) Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci USA 107:21737–21742PubMedCrossRef

38.

Thussbas C, Nahrig J, Streit S et al (2006) FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer. J Clin Oncol 24:3747–3755PubMedCrossRef

39.

Bange J, Prechtl D, Cheburkin Y et al (2002) Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer Res 62:840–847PubMed

40.

Sharpe R, Pearson A, Herrera-Abreu MT et al (2011) FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res 17:5275–5286PubMedCrossRef

41.

Gelsi-Boyer V, Orsetti B, Cervera N et al (2005) Comprehensive profiling of 8p11–12 amplification in breast cancer. Mol Cancer Res 3:655–667PubMedCrossRef

42.

Gowardhan B, Douglas DA, Mathers ME et al (2005) Evaluation of the fibroblast growth factor system as a potential target for therapy in human prostate cancer. Br J Cancer 92:320–327PubMed

43.

Martin AJ, Grant A, Ashfield AM et al (2011) FGFR2 protein expression in breast cancer: nuclear localisation and correlation with patient genotype. BMC Res Notes 4:72PubMedCrossRef

44.

Zammit C, Barnard R, Gomm JC et al (2001) Altered intracellular localization of fibroblast growth factor receptor 3 in human breast cancer. J Pathol 194:27–34PubMedCrossRef

45.

Kuroso K, Imai Y, Kobayashi M et al (2010) Immunohistochemical detection of fibroblast growth factor receptor 3 in human breast cancer: correlation with clinicopathological/molecular parameters and prognosis. Pathobiology 77:231–240PubMedCrossRef

46.

Zhu X, Asa SL, Ezzat S (2010) Genetic and epigenetic mechanisms down-regulate FGF receptor 2 to induce melanoma-associated antigen A in breast cancer. Am J Pathol 176:2333–2343PubMedCrossRef

47.

Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–1093PubMedCrossRef

48.

Marian C, Ochs-Balcom HM, Nie J et al (2010) FGFR2 intronic SNPs and breast cancer risk: associations with tumor characteristics and interactions with exogenous exposures and other known breast cancer risk factors. Int J Cancer 129:702–712PubMedCrossRef

49.

Garcia-Closas M, Chanock S (2008) Genetic susceptibility loci for breast cancer by estrogen receptor status. Clin Cancer Res 14:8000–8009PubMedCrossRef

Title: Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer
Authors: Juan P. Cerliani
Silvia I. Vanzulli
Cecilia Pérez Piñero
María C. Bottino
Ana Sahores
Myriam Nuñez
Romina Varchetta
Rubén Martins
Eduardo Zeitlin
Stephen M. Hewitt
Alfredo A. Molinolo
Claudia Lanari
Caroline A. Lamb
Publication date: 01-06-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1883-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

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 3/2012

Beyond taxanes: the next generation of microtubule-targeting agents

Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition

Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients

Benign thyroid disease is associated with breast cancer: a meta-analysis

Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: The Korean Hereditary Breast Cancer (KOHBRA) Study

Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival

Keynote webinar | Spotlight on antibody–drug conjugates in cancer