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Breast cancer is an important health care problem since it is the most frequently occurring cancer (1 out of about 10 women) and among the major causes of death in women in the Western world. Despite many studies, breast carcinogenesis is still not well understood. Although many breast cancer risk factors have been identified, they do not easily translate into molecular changes that help to understand why normal breast cells derail to form early lesions that then accumulate further genetic events that make them eventually progress to cancer. Discussing these risk factors is therefore beyond the scope of this chapter. We will also stay away from providing endless lists of possibly relevant individual genetic aberrations. Rather, we will try to integrate the fairly fragmentary knowledge of genetic aberrations and changes in gene expression into progression models based on long-standing morphologic progression models. This is quite challenging, since breast cancer is a very heterogeneous disease, far beyond the so-called ductal and lobular lesions that are best known. Nevertheless, these morphologic progression models have proven to provide a proper framework to depict and understand how different early lesions may progress to cancer, and help to place relevant genetic changes into the different progression routes to cancer. Further, they have been proven to be clinically relevant, in the sense that relative risk of these lesions to progress to cancer is known from long-term follow-up studies. This has become the base for clinical management of such lesions when found in a breast biopsy, for example, after a mammographic abnormality on breast screening.

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The epithelial progression routes comprise those for ductal lesions, columnar cell lesions, lobular lesions, papillary lesions, apocrine lesions, mucinous lesions, medullary lesions, metaplastic lesions, secretory lesions, and adenomyoepithelial lesions. However, in this chapter we will focus on conceptual issues that are shared by the progression routes for these different lesions, and then shortly try to place different precursors within progression routes for epithelial breast cancer. In addition, carcinogenesis in hereditary cancer syndromes will be discussed separately.

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The fibroepithelial route comprises progression from fibroadenoma and related lesions to malignant phyllodes tumors. Before going into some of these individual progression routes in detail, we will provide a general framework for breast carcinogenesis, integrating morphologic, immunohistochemical, and genetic findings.

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The pathogenesis of invasive breast cancer has been under debate for decades, and many progression models have been proposed, incorporating the epidemiologic and genetic findings at the respective times. However, some of these models and concepts were not able to generate a global understanding for many aspects of this threatening disease.

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In the general sense, (sporadic) breast carcinogenesis is not essentially different from carcinogenesis of other epithelial malignancies. Tumor suppressor gene inactivation through promoter methylation is likely among the earliest events in breast carcinogenesis.1,2 Besides, loss of heterozygosity may occur already early in breast carcinogenesis as a means of inactivating crucial genes.3,4

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