The MCF10 series of cell lines was derived from benign breast tissue from a woman with fibrocystic disease. The MCF10 human breast epithelial model system consists of mortal MCF10M and MCF10MS (mortal cells grown in serum-free and serum-containing media, respectively), immortalized but otherwise normal MCF10F and MCF10A lines (free-floating versus growth as attached cells), transformed MCF10AneoT cells transfected with T24 Ha-ras, and premalignant MCF10AT cells with potential for neoplastic progression. The MCF10AT, derived from xenograft-passaged MCF10-AneoT cells, generates carcinomas in approximately 25% of xenografts. We now report the derivation of fully malignant MCF10CA1 lines that complete the spectrum of progression from relatively normal breast epithelial cells to breast cancer cells capable of metastasis. MCF10CA1 lines display histologic variations ranging from undifferentiated carcinomas, sometimes with focal squamous differentiation, to well-differentiated adenocarcinomas. At least two metastasize to the lung following injection of cells into the tail vein; one line grows very rapidly in the lung, with animals moribund within 4 weeks, whereas the other requires 15 weeks to reach the same endpoint. In addition to variations in efficiency of tumor production, the MCF10CA1 lines show differences in morphology in culture, anchorage-independent growth, karyotype, and immunocytochemistry profiles. The MCF10 model provides a unique tool for the investigation of molecular changes during progression of human breast neoplasia and the generation of tumor heterogeneity on a common genetic background.

Numerous models have been developed to address key elements in the biology of breast cancer development and progression. No model is ideal, but the most useful are those that reflect the natural history and histopathology of human disease, and allow for basic investigations into underlying cellular and molecular mechanisms. We describe two types of models: those that are directed toward early events in breast cancer development (hyperplastic alveolar nodules [HAN] murine model, MCF10AT human xenograft model); and those that seek to reflect the spectrum of metastatic disease (murine sister cell lines 67, 168, 4T07, 4T1). Collectively, these models provide cell lines that represent all of the sequential stages of progression in breast disease, which can be modified to test the effect of genetic changes.

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It is now appreciated that cancers can be composed of multiple clonal s~bpopulations of cancer cells which differ among themselves in many properties, including karyotype, growth rate, ability to metastasize, immunological characteristics, production and expression of markers, and sensitivity to therapeutic modalities. Such tumor heterogeneity has been demonstrated in a wide variety of animal tumors of differing etiology, tissue and cellular origin, and species. It has been shown in autochthonous, as well as transplanted, tumors. Similar results have been reported for human cancers, although much of the evidence that heterogeneity of human cancers, also reflects, at least in part, the existence of clonal subpopulations, is still indirect. Heterogeneity is not a unique property of malignancy. Preneoplastic tumors, as well as normal tissues, are also composed of cellular subpopulations.Proposed mechanisms for the origin of tumor heterogeneity include coalescence of multiple loci of cancer clones and the generation of diverse subpopulations from a single clone. This latter process could be due to genetic errors arising from classical genetic mechanisms or to the production of cellular variants as in normal tissue differentiation. Indeed, certain tumor subpopulations have been shown to produce variants at high frequency. In some cases this frequency can be modified by environmental circumstances. Nontumor cells may also contribute to production of cancer cell variants, perhaps, in the case of infiltrating phagocytic cells, by producing mutagens or by somatic hybridization with cancer cells. Production of tumor cell variants is a dynamic process which can occur at any time.Although tumors are mixed populations of cells, knowledge of the characteristics of individual components is not sufficient to predict the behavior of the whole. Individual cancer subpopulations can interact to affect each other's growth, immunogenicity, ability to metastasize, sensitivity to drugs, and clonal stability. The existence of multiple, interactive subpopulations provides a basis for the well-known phenomenon of 'tumor progression' in which tumors undergo qualitative changes in characteristics over the course of time. Selection of subpopulations better able to survive changing environmental circumstances allows for such changes as autonomy in regard to endogenous growth regulation, more "malignant' behavior, and loss of response to therapy. Tumor subpopulation interactions may play a regulatory role in this process.Tumor heterogeneity has obvious consequences to the design of effective therapy. It provides one rationale for combination therapies and suggests that initial treatment should be early and comprehensive. The continuing emergence of new clones suggests that treatment which is unsuccessful at one point might be effective later. Assays to predict effective therapy for individual patients need to address the multiplicity of tumor subpopulations and the ability of these subpopulations to influence each other. Subpopulation interacti...