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. 2012 Jun;133(3):997-1008.
doi: 10.1007/s10549-011-1883-6. Epub 2011 Nov 29.

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

Juan P Cerliani  1 , 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
Affiliations

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

Juan P Cerliani et al. Breast Cancer Res Treat. 2012 Jun.

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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Conflict of interest statement

Conflict of interest The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Expressions of FGFRs in murine mammary gland development. Immunohistochemical analysis of virgin (V), pregnant (P), lactating (L), and involuting (I) murine mammary glands with FGFR-1, −2, −3, and −4. Nuclei were counterstained with methyl green. Bar FGFR1–4: 50 μm
Fig. 2
Fig. 2
FGFRs’ expressions of hormone-treated murine mammary glands. Immunohistochemical analysis of virgin murine mammary glands with FGFR-1, −2, −3, and −4 treated with 20 mg of MPA or Pg and 5 mg of E2 during 1 week. Nuclei were counterstained with methyl green. Bar 15 μm
Fig. 3
Fig. 3
FGFR expression and activation state in HD and HI. a Immunohistochemical analysis of HI (C4-HI) or HD (C4-HD) murine mammary carcinomas growing in MPA-treated or untreated mice reacted with FGFR-1, −2, −3, and −4 antibodies. Nuclei were counterstained with H&E. Bar 60 μm. b Western blot analysis of whole-cell C4-HI or C4-HD tumor extracts, MPA-treated or untreated, and immunoblotted for FGFR-1, −2, −3, and −4 and β-actin. FGFRs bands were quantified, normalized to the protein content (β-actin) and expressed as arbitrary units. c Extracts were IP with the corresponding FGFR antibody or with a P-Tyr antibody as described in “Materials and methods“ section, and the immunoprecipitates were used for western blotting using both antibodies. d Western blot of C4-HI whole cell extracts transiently transfected with siRNA for FGFR-3 for 24 or 72 h. Bands were quantified and normalized to the protein content (β-actin) *P < 0.05; **P < 0.01
Fig. 4
Fig. 4
Immunohistochemical analysis of FGFR expressions of human cell lines growing in vivo. MCF-7, IBH-6, MDA-MB-231, and T47D-R2-CA tumor sections were immunostained with FGFR-1, −2, −3, and −4. Nuclei were counterstained with H&E. Bar 30 μm
Fig. 5
Fig. 5
Immunohistochemical analysis of FGFR expressions of human breast cancer samples. a FGFRs immunohistochemistry of an invasive ductal carcinoma of histological and nuclear grade: 2, mitotic index: 1, ER and PR: +. FGFR-1: Sheets and solid groups of malignant cells forming abortive glandular spaces filled with a mucinous substance. Mild immunoreactivity of isolated tumor cells (inset, arrow). Mostly inconspicuous stroma (arrow head). FGFR-2: Islands of atypical glandular cells infiltrating a loose fibroblastic stroma (arrow heads). Most of the proliferating malignant cells are immunoreactive; dense cytoplasmic brown deposits (inset). FGFR-3: Solid masses infiltrating a fibroblastic stroma (arrow heads). Atypical cells develop intracytoplasmic vacuoles. Strong cytoplasmic reactivity of atypical cells (inset). FGFR-4: Solid sheets and pseudoglands of atypical glandular epithelial cells immersed in an unremarkable loose stroma (arrow head). Most tumor cells display a faint granular cytoplasmic reactivity (inset). Bar 100 μm. b Invasive lobular carcinoma. ER and PR: +. Tumor sections were immunostained with FGFR-2 and −3. Bar 40 μm. c Four different ductal invasive carcinomas immunostained for FGFR-1, −3, and −4. I Epithelial cells display moderate cytoplasmic immunostaining for FGFR-1, II Nuclear and cytoplasmic staining. III Weak staining for FGFR-3. IV Strong epithelial cytoplasmic staining (score 3) for FGFR-4. Bar 40 μm. Nuclei were counterstained with H&E
Fig. 6
Fig. 6
Clustering analyses. a Clustering analysis of breast cancer samples. The closeness of the columns directly indicates correlation. There is a strong correlation between FGFR-2 and FGFR-3 and a weaker correlation with ER. Tissues scores: 0: green; 1: black; 2: dark red; 3: red and no available data: gray. b Percentages of expressions for FGFR-1, −2, −3, and −4 according to staining intensity (graded 0–3 as described in “Materials and methods“ section)
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