Molecular evolution of breast cancer

Abstract

Molecular analysis of invasive breast cancer and its precursors has furthered our understanding of breast cancer progression. In the past few years, new multi-step pathways of breast cancer progression have been delineated through genotypic-phenotypic correlations. Nuclear grade, more than any other pathological feature, is strongly associated with the number and pattern of molecular genetic abnormalities in breast cancer cells. Thus, there are two distinct major pathways to the evolution of low-and high-grade invasive carcinomas: whilst the former consistently show oestrogen receptor (ER) and progesterone receptor (PgR) positivity and 16q loss, the latter are usually ER/PgR-negative and show Her-2 overexpression/amplification and complex karyotypes. The boundaries between the evolutionary pathways of well-differentiated/low-grade ductal and lobular carcinomas have been blurred, with changes in E-cadherin expression being one of the few distinguishing features between the two. In addition, lesions long thought to be precursors of breast carcinomas, such as hyperplasia of usual type, are currently considered mere risk indicators, whilst columnar cell lesions are now implicated as non-obligate precursors of atypical ductal hyperplasia (ADH) and well-differentiated ductal carcinoma in situ (DCIS). However, only through the combination of comprehensive morphological analysis and cutting-edge molecular tools can this knowledge be translated into clinical practice and patient management.

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

“…This is expected, given that only breast carcinomas of histological grades 2 and 3 were present in the population and gains of 8q are rather frequent in grade 2 and 3 breast cancers (Buerger et al, 1999a, b;Roylance et al, 1999). The comparison between the genomic profiles obtained for ductal and lobular carcinomas were also in agreement with previous studies (Buerger et al, 1999b;Shelley Hwang et al, 2004;Reis-Filho et al, 2005a;Simpson et al, 2005;Stange et al, 2006): gain of 1q and deletions of 16q were the most prevalent changes in lobular carcinomas, whereas gain of 8q was significantly more frequent in grade 2 and 3 ductal carcinomas. However, we could define the smallest region of overlap of the deletions of 16q, which mapped to 16q21 -q22.1 and encompassed the region of the cadherin gene cluster, and the gain of 8q, which encompassed two regions 8q13.2 -q21.13 and 8q21.3 -qtel (Supplementary Table 3).…”

“…Recurrent gains on chromosome 1q, 8q, 11q, 17q and 20q and losses on 6q, 8p, 9p, 13q and 16q were the most prevalent changes. In addition, we confirmed the association between ER positivity and gain of 1q coupled with loss of 16q (Farabegoli et al, 2004;Reis-Filho et al, 2005a;Simpson et al, 2005) and the more prevalent deletions of 4p16 and 4p15, 5q and 17p11.2 in ERnegative tumours (Loo et al, 2004). In contrast to previous studies (Loo et al, 2004), gains of 8q24.1 (MYC) and 17q12 (HER2) were not significantly more frequent in ER-positive tumours.…”

“…On the other hand, loss of 16q23.3 -q24.1 was more frequently observed in HER2 -tumours. This would be expected given that all HER2 þ cases were of histological grade III and loss of 16q is significantly less frequently found in this group of tumours (ReisFilho et al, 2005a;Simpson et al, 2005).…”

“…Breast cancer is a heterogeneous disease comprising tumours with remarkably distinct clinical behaviour (Simpson et al, 2005). In the last 20 years, a multitude of prognostic and predictive markers have been tested, however only oestrogen receptor, progesterone receptor and HER2 are currently used to tailor the therapy of breast cancer patients (Goldhirsch et al, 2005).…”

Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions

“…Most invasive breast cancers (approximately 90%) are of the ductal or lobular histopathological type (Symmans, 2005). Numerous molecular markers have been examined for their predictive value in breast cancer prognostication, but histopathologic grade emerges as the most important indicator of longterm patient outcome (Simpson et al, 2005;Symmans, 2005). However, histopathologic grade generally correlates with the expression of genes associated with increased cell proliferation p53), growth (HER-2), and invasiveness (matrix metalloproteinases) (Mirza et al, 2002;Reed et al, 2000).…”