Differentiation and Cancer in the Mammary Gland: Shedding Light on an Old Dichotomy

Abstract

In this brief review, the development of breast cancer is discussed from the vantage of phenotypic differentiation, similar to what has been considered over the years for leukemias and melanomas, both of which express easily visible differentiation markers (Hart and Easty, 1991;Clarke et al., 1995;Lynch, 1995;Sachs, 1996;Sledge, 1996). The review is divided into a theoretical background for human breast differentiation and a discussion of recent experimental results in our laboratories with differentiation of breast epithelial cells.In the theoretical background, in situ markers of differentiation of normal breast and carcinomas are discussed with emphasis on their possible implications for tumor therapy. So far, most of the emphasis regarding differentiation therapy of tumors has been focused on the possible action of soluble factors, such as colony-stimulating factors in leukemias and retinoic acids in solid tumors Sachs, 1996). However, an emerging and promising new avenue in this area appears to point to additional factors, such as the cellular form and extracellular matrix (ECM) (Bissell et al., 1982;Bissell and Barcellos-Hoff, 1987;Ingber, 1992). The recent interest in these parameters has evolved along with an increasing understanding of the molecular composition of the ECM, and of the molecular basis of the classical findings that normal cells-in contrast to tumor cellsare anchorage dependent for survival and growth (Folkman and Moscona, 1978;Hannigan et al., 1996). We now know that this is the case for epithelial as well as fibroblastic cells, and that interaction with ECM is crucial for such regulation. Indeed, ECM and integrins are emerging as the central regulators of differentiation, apoptosis, and cancer (Boudreau et al., 1995;Boudreau and Bissell, 1996;Werb et al., 1996;Weaver, et al., 1997).In the experimental part, we elaborate on our own recent experiments with functional culture models of the human breast, with particular emphasis on how "normal" and cancer cells could be defined within a reconstituted ECM. Special attention is given to integrins, the prominent ECM receptors. We further discuss a number of recent experimental results, all of which point to the same conclusion: namely that phenotypic reversion toward a more normal state for epithelial tumors is no longer an elusive goal. Thus "therapy by differentiation" could be broadened to include not only blood-borne tumors, but also solid tumors of epithelial origin.

Tumor suppression without differentiation or apoptosis by antisense cyclin D1 gene transfer in K1735 melanoma involves induction of p53, p21WAF1 and superoxide dismutases

“…Considering that the p16-cyclin D.cdk4 pathway is usually non-functional in melanoma tumors, 16,34 and the lower cyclin D1 protein expression in non-proliferating melanocytes than in melanomas, 19,38 our data also suggests that use of melanocyte-specific promoters 39 preceding an antisense cyclin D1 sequence could provide the basis for a targeted retroviral vector potentially helpful against melanomas refractory to differentiation 25 and other traditional therapies.…”

“…24 However, reversal of tumorigenicity by an antisense cyclin D1 cDNA, which activates the p53-p21WAF1 pathway and restores anti-oxidant activities, occurs without apparent cell death or concomitant increase in pigmentation or tyrosinase expression in K1735 melanoma cells, which are properties characteristic of melanocytic cell differentiation. 18 Our findings imply that in vivo and in vitro growth suppression of tumors refractory to differentiation 25 can occur independently of increased differentiation 20 and without cell death by induction of tumor growth retardation 26 mediated by an increase in p53 and superoxide dismutases.…”

Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene

“…A logical extension of this concept is that cancer cells can be induced to differentiate by suitable treatment to reactivate endogenous growth control mechanisms, which in a mutated and genetically damaged cancer cell context can culminate in apoptosis Leszczyniecka et al, 2001). This possibility has been addressed experimentally utilizing various model systems with the capacity to undergo in vitro differentiation (Lovat et al, 1997;Petersen et al, 1998;Wang and Chen, 2000;Leszczyniecka et al, 2001). Analysis of gene expression changes in differentiation therapy models provides a powerful experimental tool for delineating and understanding biochemical and molecular events mediating growth arrest of transformed cells Huang et al, 1999a, b;Jiang et al, 2000;Zhang et al, 2000).…”

“…In addition, studies in such systems can lead to identification of specific molecules, which are important activators of the terminal differentiation process. Such molecules, in addition to being important analytical tools, also have therapeutic potential in anticancer gene therapy or drug design (Petersen et al, 1998;Zhang et al, 2000;Su et al, 2001;Fisher et al, 2003).…”

Synthesis and evaluation of new 5-fluorouracil antitumor cell differentiating derivatives

“…5 The differentiation therapy has been successfully used in patients with blood-borne tumours and only a few number of studies have shown effectiveness in solid tumours. 6 Previously, uracil analogous, 7 new retinoid derivatives 3c or butyric acid prodrugs 5 have been described to induce differentiation.…”