The molecular pathology of breast cancer progression

Abstract

The current model of human breast cancer progression proposes a linear multi-step process which initiates as flat epithelial atypia (FEA), progresses to atypical ductal hyperplasia (ADH), evolves into DCIS and culminates in the potentially lethal stage of invasive ductal carcinoma. For several decades a major challenge to human breast cancer research has been the identification of the molecular alterations associated with the different stages of breast cancer progression. Until recently, progress in attaining this goal has been hampered by technical limitations associated with applying advanced molecular technologies to the microscopic preinvasive stages of breast tumorigenesis. Recent advances in comprehensive, high-throughput genetic, transcriptomic and epigenetic technologies in combination with advanced microdissection and ex vivo isolation techniques have provided for a more complete understanding of the complex molecular genetic and molecular biological inter-relationships of the different stages of human breast cancer evolution. Here we review the molecular biological data suggesting that breast cancer develops and evolves along two distinct molecular genetic pathways. We also briefly review gene expression and epigenetic data that support the view of the tumour microenvironment as an important co-conspirator rather than a passive bystander during human breast tumorigenesis.

Figure 1

Models of breast cancer progression. (A) The classic model of breast cancer progression of the ductal type proposes neoplastic evolution initiates in normal epithelium (normal), progresses to flat epithelial atypia (FEA), advances to atypical ductal hyperplasia (ADH), evolves to ductal carcinoma in situ (DCIS) and culminates as invasive ductal carcinoma (IDC). Immunohistochemical, genomic and transcriptomic data strongly support the evidence of a continuum from FEA to ADH, DCIS and IDC, indicating FEA as the potential non-obligate precursor of ADH. In contrast, the alternative model of breast ductal cancer progression (B), which was mostly based on epidemiologic and morphologic observations, proposes usual ductal hyperplasia (UDH) instead of FEA as direct precursor to ADH. However recent studies have shown that UDH has a distinct immunohistochemical and molecular profile from FEA and probably represents a biologic dead end. (C) The model of lobular neoplasia proposes a multistep progression from normal epithelium to atypical lobular hyperplasia, lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC).

Figure 2

Schematic of the hierarchy of normal breast epithelial development with possible links to the tumor-initiating cells of the different molecular cancer subtypes and to the role of steroid hormones in the control of the mammary stem and progenitor cells. The breast stem cell (BSC) with intrinsic self-renewal potential (curved block arrow) differentiates into a common progenitor that gives rise to committed myoepithelial and luminal progenitors that ultimately differentiate into myoepithelial, luminal and ductal epithelial cells (left hand side). The subpopulations of normal cells show a gene signatures that are similar to that of previously described cancer molecular subtypes (right hand side) providing evidence of a link (bold arrows) between the two. While the luminal progenitor subpopulation is enriched in the HER2 (HER2+) and basal-like cancers (HER2−), the more differentiated ductal epithelial cell subpopulation is enriched in the luminal (A/B) tumors. Mammary stem cells and potentially progenitor cells subpopulations are indirectly profoundly responsive to steroid hormone signaling despite their estrogen and progesterone receptors negative (ER− and PR−) phenotype. During the reproductive cycle and pregnancy the surge of progesterone stimulates the differentiated ductal epithelial cells to release the RANK Ligand that elicits expansion of the stem cell population, via paracrine signaling (blue arrows).

Figure 3

Divergent evolutionary pathways of breast cancer progression. Genomic and transcriptomic data in combination with morphological and immunohistochemical data stratify the majority of breast cancers into a “low-grade-like” molecular pathway and a “high-grade-like” molecular pathway. The low-grade-like pathway (left hand side) is characterized by recurrent chromosomal loss of 16q, gains of 1q, a low-grade-like gene expression signature, and the expression of estrogen and progesterone receptors (ER+ and PR+). The progression (vertical arrows) along this pathway (green rectangles) culminates with the formation of low and intermediate grade invasive ductal, (LG IDC and IG IDC) and invasive lobular carcinomas including both the classic (ILC) and the pleomorphic variant (pILC). The tumors arising from the low grade pathway are classified as luminal consisting of a continuum of gene expression frequently associated with the absence (luminal A) or presence of HER2 expression (luminal B). The vast majority of ILCs and pILCs and their precursors cluster together within the luminal subtype. The high grade-like gene expression molecular pathway (right hand side) is characterized by recurrent gain of 11q13 (+11q13), loss of 13q (13q−), expression of a high-grade-like gene expression signature, amplification of 17q12 (17q12AMP), and lack of estrogen and progesterone receptors expression (ER− and PR−). The progression along this pathway (red rectangles) includes intermediate and high grade ductal carcinomas that are stratified as HER2, or basal-like, depending on the expression/amplification of HER2. The molecular apocrine subtype, characterized by the lack of ER expression and presence of AR expression, arises from the high grade pathway. The model also depicts intra-pathway tumor grade progression (horizontal arrows). Abbreviations: ALH (atypical lobular hyperplasia), LCIS (lobular carcinoma in situ), pALH (pleomorphic atypical lobular hyperplasia), pLCIS (pleomorphic lobular carcinoma in situ), FEA (flat epithelial atypia), ADH (atypical ductal hyperplasia), Basal (basal-like), mApocrine (molecular Apocrine). +/− HER2 in which the “–”sign is bold indicates that the majority of tumors in the pathway lack HER2 overexpression. (This figure is adapted from [112] ).