The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer

Abstract

Current hormonal therapies have benefited millions of patients with breast cancer. Their success, however, is often temporary and limited to a subset of patients whose tumors express estrogen receptor alpha (ER). The therapies are entirely ineffective in ER-negative disease. Recent studies suggest that there are many biological pathways and alterations involved in determining whether ER is expressed and how it is regulated during breast cancer evolution. Improving hormonal therapies, in addition to perfecting current strategies, will also target these newly discovered pathways and alterations, and others yet to be found. The present commentary will briefly highlight a few important observations and unanswered questions regarding ER status and growth regulation during breast cancer evolution, which hopefully will help to stimulate new thinking and progress in this important area of medial research.

Figure 1

Examples illustrating typical levels of estrogen receptor alpha (ER) expression in normal and premalignant breast epithelial cells (dark nuclei, ER-positive as assessed by immunohistochemistry). On average, (a) normal premenopausal terminal duct lobular units contain about 30% ER-positive cells. In contrast, nearly all cells express very high levels of ER in the majority of premalignant breast lesions, including (b) atypical ductal hyperplasia, (e) atypical lobular hyperplasia, (f) and lobular carcinoma in situ. Ductal carcinoma in situ is an exception, showing a continuum of ER expression ranging from (c) very high levels characteristic of histologically lower-grade lesions to very low levels characteristic of higher-grade lesions, including a substantial subset (~25%) that is entirely ER-negative (d).

Figure 2

Examples illustrating the wide range of estrogen receptor alpha (ER) expression characteristic of invasive breast cancers (IBCs) (dark nuclei, ER-positive as assessed by immunohistochemistry). (a) A substantial (~25%) subset of IBCs does not contain any ER-expressing cells. The majority (~75%), however, do contain ER-expressing cells, but the proportion varies on an evenly distributed continuum ranging from (b, c) very low, to (d, e) intermediate, to (f) very high.

Figure 3

Kaplan-Meyer curves illustrating the surprising skewed relationship between estrogen receptor alpha (ER) status (immunohistochemistry [IHC] scores) and clinical outcome (disease-free survival [DFS]) in patients (n = 777) with invasive breast cancer treated with adjuvant tamoxifen therapy (reproduced with permission) [7]. Tumors with as few as 1–10% ER-positive cells (IHC score = 3) respond far better than ER-negative tumors (IHC score = 0 and 2 corresponding to none and < 1% ER-positive cells, respectively), and nearly as well as tumors with much higher ER content (IHC score = 4–8 corresponding to > 10% to 100% ER-positive cells). The observation that tumors with a low proportion of ER-positive cells respond almost as well as those with a very high proportion raises important questions about the nature of stem cells that could produce and sustain such biologically diverse but clinically similar populations.

Figure 4

Discordant estrogen receptor alpha (ER) expression in occasional breast cancers strongly suggests that mechanisms exist that are responsible for the evolution of ER-negative from ER-positive tumor cells. For example, nearly all invasive breast cancers (IBCs) contain varying proportions of ductal carcinoma in situ (DCIS), probably representing residual precursors. (a) In ~5% of ER-negative IBCs, the DCIS component is strongly ER-positive. As another example, histologically high-grade DCIS are often (~70%) ER-negative. (b) A diligent search can reveal foci of lower-grade/ER-positive DCIS in the same breast, which may be a precursor to the higher-grade/ER-negative component.