Glycodelin reduces breast cancer xenograft growth in vivo

Abstract

Malignant growth is characterized by loss of cell differentiation, uncontrolled proliferation and resistance to apoptosis. Many tumor suppressor genes that protect cells against malignant transformation regulate cell differentiation. Here, we show for the first time that glycodelin, a differentiation-related protein, reduces breast cancer tumor growth in vivo. We found that glycodelin cDNA-transfected MCF-7 breast cancer cells showed a differentiated phenotype and produced smaller tumors in mouse mammary fat pads compared with control-transfected cells. Glycodelininduced differentiation was associated with reduced expression of oncogenes and increased expression of tumor suppressor genes. Our results suggest that glycodelin acts as a tumor suppressor in breast cancer. This may explain its reported association with a more favorable prognosis in some cancers. ' 2008 Wiley-Liss, Inc.Key words: breast cancer; differentiation; glycodelin; tumor growth; xenograft tumor Cancers may arise through several mechanisms. The main features include loss of cell differentiation, uncontrolled proliferation and resistance to apoptosis. 1 In breast cancer cells, the malignant phenotype can be reversed back to normal by various mechanisms, such as blocking of b 1 integrin and epidermal growth factor receptor by antibodies, and inhibition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase pathways. 2,3 In addition, many of the proteins that protect the cells against malignant transformation also regulate cell differentiation. 4 Glycodelin is a lipocalin protein mainly expressed in reproductive tissues. 5 It is also expressed in the bone marrow and in many normal and malignant epithelial cells, including those of normal and malignant breast tissues. [6][7][8][9][10][11] In the reproductive and immune systems, glycodelin is involved in cell recognition. 12 The relationship of glycodelin with epithelial differentiation is well established in the normal endometrium, in which temporal glycodelin expression is progesterone regulated. 5 This is also the case in cultured endometrial carcinoma cell lines. 13,14 Recent reports suggest that glycodelin actually drives epithelial differentiation. 8,13,15 In ovarian serous carcinoma, glycodelin is more frequently expressed in well differentiated than in poorly differentiated carcinomas, and it correlates with better survival. 9 Preliminary results suggest that glycodelin expression is associated with better prognosis also in breast cancer. 11 We investigated the molecular changes associated with glycodelin-induced differentiation. Given that the surrounding microenvironment plays a role in tumor development, we used various cell culture conditions and a mouse xenograft model to elucidate the effects of glycodelin on tumor growth in vivo. We found that, in experimental preclinical mouse model, glycodelin-producing human breast carcinoma cells form smaller tumors than the glycodelin nonproducing control cells do. Material and methodsThe study was approved by the Instituti...

GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis

“…Interestingly, the 30 most differentially regulated genes (Supplementary Tables 1 and 2) included several genes related to breast cancer metastasis and malignancy (Goodison et al, 2005;Minn et al, 2005;Buess et al, 2007;Gupta et al, 2007b;Hautala et al, 2008). The genes upregulated in GATA3-overexpressing cells included inhibitors of breast cancer growth and metastasis, such as PAEP (progestagenassociated endometrial protein) (Glycodelin) and DLC1 (deleted in liver cancer 1), whereas the prometastatic genes, ID1, ID3, LY6E, KRTHB1 and RARRES3, as well as the interferon-response genes, MX1, OAS1, G1P3 and IFI44L, were found to be downregulated in the presence of high GATA3 expression.…”

“…Particularly, ID1 and ID3, were shown to facilitate secondary outgrowth of breast tumors metastases in the lungs (Gupta et al, 2007b), which is in agreement with the role of GATA3 identified here. Of note, DLC1, which inhibits lung metastasis of breast cancer cells (Goodison et al, 2005) and PAEP (glycodelin), which inhibits breast cancer growth (Hautala et al, 2008), were among the genes upregulated by GATA3. Hence, the combined repression of ID1/3, LY6E, KRTHB1 and RARRES3 and induction of DLC1 and PAEP in response to GATA3 overexpression may play a significant role in preventing lung metastasis.…”

Glycodelin in reproductive endocrinology and hormone-related cancer

“…In hormone-responsive tumours, glycodelin-induced differentiation is related to the decreased expression of oncogenes and an increased expression of tumour suppressor genes, emphasising the tumour suppressor nature of glycodelin (Table 4). The role of glycodelin glycosylation in the transfected tumour cells is still an unresolved issue that may account for the diverse responses in the cell lines studied (104). But interestingly, glycodelin-inducing SAHA has been reported to act as a trans-differentitation agent in MCF-7 breast cancer cells (105).…”

Glycodelin expression associates with differential tumour phenotype and outcome in sporadic and familial non-BRCA1/2 breast cancer patients

“…Several studies have shown that glycodelin is not only associated with differentiated epithelium, but it also induces cell differentiation in endometrial and breast cancer cells [5][6][7][8][9][10][11]. Glycodelin differentiates MCF-7 breast cancer cells towards normal, less malignant direction [6,7].…”