Estrogen receptor-β is expressed in stromal cells of fibroadenoma and phyllodes tumors of the breast

Department of Biomedical Science and Human Oncology, University of Torino, Torino, Italy.
Modern Pathology (Impact Factor: 6.19). 05/2006; 19(4):599-606. DOI: 10.1038/modpathol.3800574
Source: PubMed


An estrogen dependency has been suggested for the growth of fibroadenomas: however, thus far, none of the steroid hormone receptors acting on breast tissues has been demonstrated in the stroma of breast fibroepithelial lesions. In this study, the expression of estrogen receptor (ER)- and - was investigated by immunohistochemistry in 33 fibroadenomas and in 30 benign, three borderline and seven malignant phyllodes tumors, all with spindle cell growth and in one distant metastasis. In addition, the presence of ER- mRNA and its variants was evaluated by RT-PCR in microdissected stroma. The possible correlation between hormone receptor expression and differentiation processes of stromal cells was investigated by smooth muscle actin and calponin immunostaining. ER- was the only hormone receptor expressed by stroma of fibroadenomas and phyllodes tumors, both at protein and mRNA level. The highest percentage of ER- was observed in fibroadenomas with cellular stroma and in phyllodes tumors. In both lesions, ER--positive stromal cells showed expression of smooth muscle actin and/or calponin, as demonstrated by double immunostaining. In addition, the mean age at diagnosis was significantly lower in patients with ER--positive vs ER--negative fibroadenomas. In contrast, in phyllodes tumors, ER- expression was higher in older patients. In conclusion, (i) only ER- is detected in the stroma of fibroadenomas and phyllodes tumors; (ii) its expression correlates with the expression of smooth muscle markers and suggests a role of ER- in myofibroblastic differentiation of stromal cells. These two results, together with the young age of patients carrying fibroadenomas with highly ER--positive stroma cells, may further indicate a hormone-receptor mechanism involved in regulating the growth of fibroadenomas. Conversely, the older age of patients with ER--rich phyllodes tumors suggests that mechanisms, probably independent from estrogen stimulation, act on the growth of these tumors.

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Available from: Anna Sapino, Apr 23, 2014
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    • "Fibroadenoma is a biphasic lesion of the breast characterized by proliferation of both epithelial and stromal components of the terminal ductal unit. Proliferation of stromal cells is commonly considered the primary event in the development of a fibroadenoma, followed by secondary proliferation of epithelial cells [1]. Most fibroadenomas are considered to be the result of hyperplastic processes involving connective tissue of lobular units [2]. "
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    ABSTRACT: Background Fibroadenomas are benign human breast tumors, characterized by proliferation of epithelial and stromal components of the terminal ductal unit. They may grow, regress or remain unchanged, as the hormonal environment of the patient changes. Expression of antigen TF in mucin or mucin-type glycoproteins and of galectin-3 seems to contribute to proliferation and transformations events; their expression has been reported in ductal breast cancer and in aggressive tumors. Findings Lectin histochemistry, immunohistochemistry, and immunofluorescence were used to examine the expression and distribution of antigen TF and galectin-3. We used lectins from Arachis hypogaea, Artocarpus integrifolia, and Amaranthus lecuocarpus to evaluate TF expression and a monoclonal antibody to evaluate galectin-3 expression. We used paraffin-embedded blocks from 10 breast tissues diagnosed with fibroadenoma and as control 10 healthy tissue samples. Histochemical and immunofluorescence analysis showed positive expression of galectin-3 in fibroadenoma tissue, mainly in stroma, weak interaction in ducts was observed; whereas, in healthy tissue samples the staining was also weak in ducts. Lectins from A. leucocarpus and A. integrifolia specificaly recognized ducts in healthy breast samples, whereas the lectin from A. hypogaea recognized ducts and stroma. In fibroadenoma tissue, the lectins from A. integrifolia, A. Hypogaea, and A. leucocarpus recognized mainly ducts. Conclusions Our results suggest that expression of antigen TF and galectin-3 seems to participate in fibroadenoma development.
    Full-text · Article · Dec 2012 · BMC Research Notes
    • "Our patient was diagnosed at perimenopausal period (49 years old), in agreement with the eight previous cases (median age at diagnosis: 52.7 ± 14.8 years), roughly similar to the median age of diagnosis of phyllode tumor, near 44 years [15]. Unlike breast carcinoma, where IGF-2 can activate estrogen receptor in a crosstalk manner [17], there is no established link between estrogen exposition and the growth of phyllode tumors [18] [19]. Thus, only few cases have reported hormonal therapy in phyllode therapy, without significative effect. "
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    ABSTRACT: Objective: We report an exceptional case of non-islet cell tumor-induced hypoglycemia (NICTH) secondary to "Big"-IGF-2 oversecretion due to a giant phyllode tumor of the breast. Clinical presentation: A 49-year-old woman was admitted in emergency for brutal neurologic defect revealing severe hypoglycemia. Several similar episodes were observed throughout hospitalization, requiring continue perfusion of hypertonic glucose solution. Beside these metabolic disorders, we observed a giant and hard tumor of the left breast (about 30cm in diameter). Interpretation: Supplementary blood analysis revealed serum levels of C-peptide and insulin suppressed during hypoglycemia, excluding the possibility of either endogenous or exogenous hyperinsulinism. Low plasma levels of GH and IGF-1 were found, suggesting a negative feedback loop on somatotroph axis function. Therefore, the hypothesis of an insulinomimetic compound released by tumor cells was evoked because of abnormal presence of high-weight and immature form of IGF-2 (called "Big"-IGF-2) in the serum identified by western immunoblot analysis. A left mastectomy was performed and completely restored glucose homeostasis and confirmed the paraneoplastic origin of hypoglycemia because of markedly elevated expression of IGF-2 mRNA (qPCR) within the tumor cells. Finally, the anatomopathology analysis diagnosed a mesenchymatous tumor, namely a high-grade phyllode sarcoma of the breast. Conclusion: Although NICTH due to "Big"-IGF-2 overproduction is a rare phenomenon, mainly observed in case of mesenchymatous tumor, it should be considered in presence of severe hypoglycemia with voluminous tumor and without hyperinsulinism.
    No preview · Article · Aug 2012 · Annales d Endocrinologie
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    ABSTRACT: Breast cancer is a hormone-based disease with numerous factors contributing to the lifetime risk of developing the disease. While breast cancer risk is reduced by nearly 50% after one full term pregnancy, women over the age of 25 have a significantly greater risk of developing breast cancer immediately following parturition compared to their nulliparous counterparts. It is widely presumed that the increased risk of developing breast cancer following pregnancy is due to the ability of pregnancy-associated hormones to promote the further proliferation of an initiated target cell population. It is surprising however, that the majority of breast cancers that develop following pregnancy lack appreciable expression of either the estrogen or progesterone receptors. This important observation suggests that if hormones play a part in promoting breast cancer following pregnancy, they may not be doing so through direct binding to hormone receptor molecules expressed by breast cancer cells. To reconcile this conceptual conflict we investigated the hypothesis that steroid hormones promote the outgrowth of ER-negative cancers by influencing host cell types distinct from the breast epithelium itself. We demonstrated that increasing the levels of circulating estrogens is sufficient to promote the formation and progression of ER-negative cancers while, pharmacologically inhibiting estrogen synthesis following pregnancy prevents ER-negative tumor formation. Moreover, we demonstrate that the effects of estrogen act via a systemic increase in host angiogenesis, in part through increased mobilization and recruitment of bone marrow stromal derived cells into sites of angiogenesis and to a growing tumor mass. Taken together, these data suggest that estrogen may promote the growth of ER-negative cancers by acting on cells distinct from the cancer cells to stimulate angiogenesis.
    No preview · Article · Jan 2007 · The Journal of Steroid Biochemistry and Molecular Biology
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