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

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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.

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Acknowledgments

The authors thank Julieta Bolado, Bruno Luna, and Pablo DoCampo for their excellent technical assistance. The authors are also grateful to Dr. Ciriano, Roche Argentina, and Dr. Acosta for evaluating Her2; and to Dr Luthy for providing the IBH-6 cell line. MCB received an ICRETT Fellowship from the UICC permitting training in Dr Gutkind’s laboratory at NIH. This study was supported by Sales Foundation, SECyT (PICT 08, No. 989), and CONICET (PIP 2010-2012 N°692). Dr. Hewitt and Dr Molinolo are supported by the Intramural Research Program of the NCI, and the NIDCR from the National Institutes of Health, respectively. JPC, CPP, MCB, AS, and CAL carried out experiments. SIV and AAM analyzed breast cancer samples. MN carried out the statistical analysis of human samples. RV, RM, and EZ provided the cancer samples. SMH prepared the mouse tissue array. CL and CAL conceived the experiments and wrote the paper. All the authors gave final approval to the submitted version.

Conflict of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Institute of Experimental Biology and Medicine (IBYME), CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina

    Juan P. Cerliani, Cecilia Pérez Piñero, María C. Bottino, Ana Sahores, Claudia Lanari & Caroline A. Lamb

  2. NIDCR, NIH, Bethesda, MD, USA

    Alfredo A. Molinolo

  3. National Academy of Medicine, Buenos Aires, Argentina

    Silvia I. Vanzulli

  4. Policlínica Bancaria, Buenos Aires, Argentina

    Romina Varchetta, Rubén Martins & Eduardo Zeitlin

  5. Mathematics Department, University of Buenos Aires, Buenos Aires, Argentina

    Myriam Nuñez

  6. National Cancer Institute, NIH, Bethesda, MD, USA

    Stephen M. Hewitt

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  1. Juan P. Cerliani
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  3. Cecilia Pérez Piñero
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Correspondence to Caroline A. Lamb.

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Cerliani, J.P., Vanzulli, S.I., Piñero, C.P. et al. Associated expressions of FGFR-2 and FGFR-3: from mouse mammary gland physiology to human breast cancer. Breast Cancer Res Treat 133, 997–1008 (2012). https://doi.org/10.1007/s10549-011-1883-6

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