Breast cancer precursors: lessons learned from molecular genetics

Abstract

The question how breast cancer evolves has been subject to many studies, but many details of the molecular pathogenesis of sporadic type breast cancer are still unknown; this applies both to hormone-dependent and hormone-independent breast cancer. However, histopathologic, genetic, and epidemiological studies have provided good evidence that almost all types of breast cancer are preceded by noninvasive precursor lesions [ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS)] that share many molecular similarities with invasive breast cancer [1, 2]. The most important contributions have come from studies involving comparative genomic hybridization (CGH), particularly with modifications that allow the use of paraffin-embedded material [3]. CGH analysis of DCIS has demonstrated a large number of gains at 1q, 5p, 6q, 8q, 17q, 19q, 20p, 20q, and Xq and losses of 2q, 5q, 6q, 8p, 9p, 11q, 13q, 14q, 16q, 17p, and 22q [4–6], and these changes are similar to invasive ductal carcinomas that are associated with large DCIS [7]. In fact, no genetic alterations specific for DCIS or invasive breast cancer were detected so far [8]. Interestingly, these DCIS lesions closely reflect the molecular subtypes of breast cancer that they precede or are associated with [9]. This has led to the distinction of two major molecular pathways in DCIS [4, 10]: a low-grade pathway that leads to the development of mostly hormonereceptor-positive tumors and a high-grade pathway. There is strong molecular evidence that precursor lesions are committed by their molecular profile to progress either to lowor high-grade carcinomas. This was repeatedly shown by comparison of molecular alterations at the genetic level of invasive breast carcinoma with adjacent ductal or lobular carcinoma in situ [4, 11], and among other evidence [12], this has lead to the hypothesis that breast cancer in general is not one but many different diseases, even at the precursor stage [13]. Today, it is evident that the neoplastic process begins earlier than at the DCIS stage, but which histological lesions are directly involved in this process is not being fully understood. More than 30 years ago, Jensen et al. [14] described a continuum of morphologic changes linking hyperplastic and metaplastic lesions including usual ductal hyperplasia (UDH) to DCIS and invasive breast cancer. This model was derived from morphologic observations on the similarity and topographic relationship of non-neoplastic lesions to in situ neoplasia and has become textbook knowledge since. Only in 2001 was it shown that this multistep model does not apply because the earliest lesion, UDH, is genetically unaltered and characterized by another cytokeratin profile than DCIS [15]. Therefore, UDH is usually not neoplastic in nature [8] and cannot be regarded as an immediate precursor of DCIS. In recent years, a new hypothesis has been put forward about what constitutes the immediate precursor for DCIS. As illustrated in Fig. 1, there is now compelling evidence that columnar cell lesions are the “missing” link between normal breast tissue and DCIS in the low-grade pathway [16, 17], and by clonality analysis of mitochondrial DNA, this was proven at least for invasive tubular carcinoma [18]. In this issue of J Mol Med, Gao et al. [19] provide further evidence to the concept of J Mol Med (2009) 87:113–115 DOI 10.1007/s00109-008-0435-y