Differentiation of breast cancer cells in vitro is promoted by the concurrent influence of myoepithelial cells and relaxin

Bani, Danièle; Riva, Alessandro; Bigazzi, Mario; Sacchi, Tatiana Bani

doi:10.1038/bjc.1994.417

Cited by 35 publications

(27 citation statements)

References 17 publications

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“…In normal or noninvasive benign mammary cells, cell-stroma contact is mediated by myoepithelial cells, which secrete relatively low levels of matrix-degrading proteinases but relatively high levels of maspin and various other antiinvasive proteinase inhibitors (30). Myoepithelial cells can also induce differentiation of breast cancer cells (31) and inhibit tumor cell invasion (29). The exclusive expression of MEPI in myoepithelial cells of normal or benign mammary gland may represent one of the major antiinvasive and antimetastatic phenotype mediated by the host defensive system.…”

Section: Discussionmentioning

confidence: 99%

Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells

Xiao

Liu

Gentz

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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A serpin was identified in normal mammary gland by differential cDNA sequencing. In situ hybridization has detected this serpin exclusively in the myoepithelial cells on the normal and noninvasive mammary epithelial side of the basement membrane and thus was named myoepithelium-derived serine proteinase inhibitor (MEPI). No MEPI expression was detected in the malignant breast carcinomas. MEPI encodes a 405-aa precursor, including an 18-residue secretion signal with a calculated molecular mass of 46 kDa. The predicted sequence of the new protein shares 33% sequence identity and 58% sequence similarity to plasminogen activator inhibitor (PAI)-1 and PAI-2. To determine whether MEPI can modulate the in vivo growth and progression of human breast cancers, we transfected a full-length MEPI cDNA into human breast cancer cells and studied the orthotopic growth of MEPI-transfected vs. control clones in the mammary fat pad of athymic nude mice. Overexpression of MEPI inhibited the invasion of the cells in the in vitro invasion assay. When injected orthotopically into nude mice, the primary tumor volumes, axillary lymph node metastasis, and lung metastasis were significantly inhibited in MEPI-transfected clones as compared with controls. The expression of MEPI in myoepithelial cells may prevent breast cancer malignant progression leading to metastasis.The serine protease plasminogen/plasmin activator(PA) system contributes significantly to extracellular proteolysis in a wide variety of physiological processes of normal development and pathological processes in the etiology of diseases such as tumor invasion and metastasis (1-2). Compelling experimental evidence has suggested an important and apparently causal role for the tumor-associated urokinase type PA (uPA) and the receptor uPAR in cancer invasion and metastasis (1-3). Consistent with its role in cancer metastasis, overexpression and unrestrained activity of u-PA has been shown clinically to be a prognostic marker in many different types of human cancer (4-10). The down-regulation of uPA may occur at the level of transcriptional regulation of the genes and through interaction with specific endogenous inhibitor serpin such as plasminogen activator inhibitor (PAI). The best characterized serpins are PAI-1 and PAI-2. Both PAI-1 and PAI-2 have been shown to inhibit extracellular matrix degradation in vitro (11-12). These results suggest that the inhibitory activity of PAIs may be important in inhibiting tumor metastatic progression leading to metastasis. In fact, administration of a recombinant PAI-2 to mice decreases tumor growth (13), whereas overexpression of either PAI-1 or PAI-2 inhibits tumor metastasis (14-15).It has been demonstrated extensively that high tumor levels of uPA and PAI-1 are statistically independent and poor prognostic factors for disease-free and overall survival in breast cancer (6,(16)(17)(18)(19). In contrast to PAI-1, high levels of PAI-2 expression may be a favorable prognostic marker in breast cancer (2-3). In breast carcinomas with h...

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Section: Discussionmentioning

confidence: 99%

Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells

Xiao

Liu

Gentz

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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“…RLX has been found to have a biphasic action on MCF-7 cells, stimulating their proliferation at low, nanomolar concentrations and inhibiting it at high, micromolar concentrations [9]. When applied to MCF-7 cells for prolonged exposure times, RLX has been shown to inhibit cell proliferation at any concentration assayed and to promote cell differentiation in terms of polarization of organelles and expression of cell-cell adhesion molecules, thus leading MCF-7 cells to acquire a phenotype reminiscent that of epithelial cells of normal mammary ducts [6,8].…”

Section: Introductionmentioning

confidence: 98%

“…Previous studies from our group have also shown that RLX influences the behavior of human breast cancer cells cultured in vitro [6][7][8][9]. In these studies we used the breast adenocarcinoma MCF-7 cell line because of its responsiveness to mammotrophic hormones [13].…”

Section: Introductionmentioning

confidence: 99%

Relaxin promotes differentiation of human breast cancer cells MCF-7 transplanted into nude mice

Bani¹,

Flagiello

Poupon

et al. 1999

Virchows Archiv

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Previous studies showed that the hormone relaxin acts on human breast cancer MCF-7 cells in vitro by modulating cell proliferation and promoting cell differentiation toward a duct epithelial phenotype. The present study was designed to investigate whether relaxin retains these properties when acting in vivo on MCF-7 cell tumors developed in athymic nude mice. Mice bearing MCF-7 cell tumors transplanted under the mammary fat pad and estrogenized to sustain tumor growth were treated systemically with relaxin (10 microg/day) for 19 days. Vehicle-treated mice were used as controls. Thirty days later, the mice were sacrificed and tumor fragments were analyzed by light and electron microscopy and immunocytochemistry. Measurements of tumor volume were recorded weekly for the overall experimental period. The results obtained indicate that relaxin treatment promotes differentiation of tumor cells towards both myoepithelial-like and epithelial-like cells, as judged by the ultrastructural features of the cells and by the increased expression of smooth muscle actin and cadherins. Measurements of tumor size and of the number of cycling cells show that relaxin, at the doses and times of exposure used in this study, does not significantly influence tumor growth and cell proliferation.

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“…The prostate-derived cells were DU-145 (Mickey et al, 1980), presumably very malignant because they were derived from a metastatic lesion of the central nervous system. The breast cancer cell line used was MCF-7 (Soule et al, 1973;Bani et al, 1994), a heterogeneous mixture of primarily undifferentiated, blast-like cells, with only a minority of cells more differentiated.…”

Section: Methodsmentioning

confidence: 99%

A 24-Phenylsulfone Analog of Vitamin D Inhibits 1α,25-Dihydroxyvitamin D₃ Degradation in Vitamin D Metabolism-Competent Cells

Lechner

Manhardt²,

Bajna³

et al. 2006

J Pharmacol Exp Ther

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The antimitotic, prodifferentiating, and proapoptotic steroid hormone, 1␣, 2 D 3 ], at supraphysiological levels has potential for tumor therapy. However, epithelial cells from tumor-prone organs such as colon, prostate, and breast express not only the vitamin D receptor, but also vitamin D hydroxylases. In contrast to normal cells, malignant cells have high basal levels of the hydroxylase 25-hydroxyvitamin D 3 -24-hydroxylase (CYP24) and, in addition, have the potential to induce CYP24 in response to 1␣,25-(OH) 2 D 3 . Because 24-hydroxylation by CYP24 would rapidly degrade the steroid hormone in the course of therapy, the enzyme activity in tumor cells should be inhibited. We demonstrate that a 24-phenylsulfone analog of 1␣,25-(OH) 2 D 3 , KRC-24SO 2 Ph-1 (S4a), rapidly and potently inhibits 24-hydroxylase activity in human tumor cells derived from colon, prostate, and mammary gland. Although enzymatic inhibition is a consequence of direct interaction, S-4a as a vitamin D analog apparently binds to the vitamin D receptor and induces CYP24 mRNA, which, however, is not translated into increased enzymatic activity. 25-Hydroxyvitamin D 3 -1␣-hydroxylase expression is not affected at all by S-4a. When both 1␣,25-(OH) 2 D 3 and S-4a are added to the cell culture, transcription of CYP24 is increased, possibly because of an increase in the half-life of the hormone. The colon cell line COGA-13 has very high levels of CYP24 and is, therefore, resistant to the action of vitamin D. Yet, S-4a imparts antimitotic activity to 1␣,25-(OH) 2 D 3 and may therefore constitute a therapeutic to stimulate the antiproliferative potential of vitamin D-based antitumor activity.

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Differentiation of breast cancer cells in vitro is promoted by the concurrent influence of myoepithelial cells and relaxin

Cited by 35 publications

References 17 publications

Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells

Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells

Relaxin promotes differentiation of human breast cancer cells MCF-7 transplanted into nude mice

A 24-Phenylsulfone Analog of Vitamin D Inhibits 1α,25-Dihydroxyvitamin D₃ Degradation in Vitamin D Metabolism-Competent Cells

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Differentiation of breast cancer cells in vitro is promoted by the concurrent influence of myoepithelial cells and relaxin

Cited by 35 publications

References 17 publications

Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells

Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells

Relaxin promotes differentiation of human breast cancer cells MCF-7 transplanted into nude mice

A 24-Phenylsulfone Analog of Vitamin D Inhibits 1α,25-Dihydroxyvitamin D3 Degradation in Vitamin D Metabolism-Competent Cells

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A 24-Phenylsulfone Analog of Vitamin D Inhibits 1α,25-Dihydroxyvitamin D₃ Degradation in Vitamin D Metabolism-Competent Cells