Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells.

Abstract

To assess the role of altered a2I18 integrin expression in breast cancer, we expressed the a2d31 integrin de novo in a poorly differentiated mammary carcinoma that expressed no detectable a2-integrin subunit. Expression of the a2131 integrin resulted in a dramatic phenotypic alteration from a fibroblastoid, spindle-shaped, non-contact-inhibited, motile, and invasive cell to an epithelioid, polygonal-shaped, contact-inhibited, less motile, and less invasive cell. Although expression of the a2 subunit did not alter adhesion to collagen, it profoundly altered cell spreading. Re-expression of the a2.1 integrin restored the ability to differentiate into gland-like structures in three-dimensional matrices and markedly reduced the in vivo tumorigenicity of the cells. These results indicate that the consequences of diminished a281-integrin expression in the development of breast cancer and, presumably, of other epithelial malignancies are increased tumorigenicity and loss of the differentiated epithelial phenotype.The role of the integrin family of heterodimeric transmembrane glycoproteins in mediating cell-cell or cell-extracellular matrix adhesion is now well established (1, 2). Viral or chemical oncogenic transformation of cells in culture results in altered morphologic phenotype and increased invasive activity accompanied by changes in integrin expression, suggesting that changes in integrin expression might contribute to changes in cell phenotype associated with malignant transformation (3, 4).The a23i integrin functions as a collagen receptor on platelets and fibroblasts and as both a collagen and laminin receptor on endothelial cells and most epithelial-cell types (5-7). In earlier immunohistochemical studies, we observed that the a231 integrin was expressed by the majority of epithelial cell types, including those of the skin, breast, lung, gastrointestinal system, and genitourinary tracts (8). The high level of a2f3i integrin expression by normal breast ducts and ductules was diminished in moderately differentiated carcinoma and markedly reduced or undetectable in poorly differentiated adenocarcinoma of the breast at both the protein and mRNA levels (9, 10). Others have confirmed that a21l-integrin expression is diminished or absent in adenocarcinoma of the breast and in other epithelial malignancies (11).To characterize the role of the a2131 integrin in breast epithelial morphogenesis and the contribution of lost a2131 expression to the malignant and invasive phenotype of mammary carcinoma cells, we re-expressed the a2131 integrin on poorly differentiated breast carcinoma cells lacking endogenous a2I31 integrin. Re-expression of the a211 integrin dramatically restored to the malignant and invasive carcinoma cells a phenotype typical of normal breast epithelial cells. We conclude that the loss of a23l-integrin expression in breast cancer directly contributes to enhanced tumorigenicity and loss of tumor-cell differentiation.

Collagen Receptor Control of Epithelial Morphogenesis and Cell Cycle Progression

“…4,5,15,47 We have also shown that reexpression of the ␣ 2 ␤ 1 integrin in a poorly differentiated, invasive breast carcinoma cell line greatly diminishes, but does not completely abrogate, the malignant potential in vivo. 15 This critical observation that ␣ 2 ␤ 1 integrin expression is required for maintenance of the differentiated epithelial phenotype and glandular differentiation in vitro has been confirmed by others. The ␣ 2 ␤ 1 integrin appears to play a similar role in the morphological differentiation of colonic epithelial cells and renal tubular epithelial cells.…”

“…2,3,[11][12][13][14] The important role that the ␣ 2 ␤ 1 integrin plays in normal epithelial differentiation has been substantiated by a number of in vitro "gain-offunction" and "loss-of-function" models. 4,5,15,16 For example, when a full-length ␣ 2 integrin cDNA was introduced into a poorly differentiated, tumorigenic murine breast cancer cell line that expressed no detectable ␣ 2 integrin subunit but high levels of the ␣ 1 integrin subunit, reexpression of the ␣ 2 ␤ 1 integrin resulted in dramatic phenotypic alteration from a fibroblastoid, spindleshaped, non-contact-inhibited cell to an epithelioid, polygonal-shaped, and contact-inhibited cell in culture. 15 Although the adhesion to collagen (mediated by the ␣ 1 ␤ 1 integrin) of the parental and control cells was comparable to the adhesion of the ␣ 2 transfectants, only the ␣ 2 transfectants formed organized structures, including alveolarlike and elongated multilayered duct-like structures in three-dimensional floating collagen gels.…”

β1 integrin promotes but is not essential for metastasis of ras-myc transformed fibroblasts

“…In transformed CHO cells, co-expression of a5 and b1 integrin rendered the cells non-tumorigenic (Giancotti and Ruoslahti, 1990). Transfection of a2 into a b1 integrin expressing mammary carcinoma cell line markedly reduced its tumorigenicity in vivo (Zutter et al, 1995). The GERM 116 cells express a5b1 integrin, yet they are as tumorigenic as the b1-de®cient parental cell line.…”

MT1-MMP promotes cell growth and ERK activation through c-Src and paxillin in three-dimensional collagen matrix

“…The present study confirms and extends our previous studies to demonstrate that MT1-MMP stimulates ERK activation in 3-D collagen, which is indispensable for proliferation of cancer cells. It is well documented that the interaction between collagen fibrils and integrin α 2 β 1 generates the growth-suppressive signals in normal epithelial or cancer cells cultured in 3-D collagen [7,[20][21][22], which can be abrogated by pericellular collagenolysis [14,15]. We represent that MT1-MMP induces c-Src activation in 3-D collagen by modulating extracellular microenvironment, which subsequently activates paxillin to scaffold signaling molecules for ERK pathway and thus leads to escape cells from growth-suppressive signals.…”