Under these circumstances, the underlying mechanisms of resistance might be expected to be common to main and secondary types. Endocrine resistance is most often thought of in clinical terms, but resistance may also occur at pathological, proliferative and molecular levels. may also occur at pathological, proliferative and molecular levels. Although these parameters are FGH10019 positively correlated, they are FGH10019 not equivalent, and disconnects between them occur relatively frequently. For example, cell cycle response and clinical response to tamoxifen and letrozole in the P024 trial were discordant in over one-third of cases despite there being a highly significant correlation between the two types of response (P= 0.00037) [2]. Similarly, the degree of FGH10019 proliferative response was not significantly different in cases responding or not responding to endocrine treatment in the IMPACT (Immediate Preoperative ‘Arimidex’ [anastrozole], Tamoxifen, or Arimidex Combined with Tamoxifen) trial [3]. Furthermore, as illustrated below, clinically resistant tumours frequently exhibit molecular responses. == Mechanisms of resistance == Theoretically, there are multiple mechanisms whereby breast cancers appear unresponsive to endocrine therapy. These include inherent tumour insensitivity to hormone therapy, activation of hormone signalling pathways by nonendocrine pathways, ineffective or compromised therapy, and domination of cell survival [4]. To determine whether these mechanisms are apparent in primary breast cancers, the neoadjuvant setting in which treatment is given with tumour still within the breast has been particularly informative. Because of relatively easy access to tumour, biopsies may be taken sequentially before and during treatment and analyzed to monitor the effects of treatment on molecular processes. Some of these studies are worthy of more detailed consideration using ER and the expression of oestrogen-regulated genes, includingKIAA0101,SERPINA3,IRS1,TFF3andTFF1as markers of (anti)oestrogenic responses, and Ki67 and expression of cell cycle/DNA synthesis genes such asCDC,CKS2,Cyclin B1,TYMSandPCNAas markers of proliferation [5-7]. Rabbit polyclonal to ACTA2 == Inherent resistance == Hormone stimulation of tumour growth is generally associated with oestrogen, whose action is mediated primarily through the ER. It follows therefore that in ER-negative tumours oestrogen is disconnected from growth (which is driven by other growth factors). Therapies directed either at oestrogen or ER are therefore unlikely to be successful in ER-negative breast cancer. This is supported by a large volume of literature, and we have reported that in the neoadjuvant setting ER-negative tumours rarely respond to a variety of endocrine therapies [8]. Additionally, as shown in Figure1, an ER-negative tumour treated electively with neoadjuvant letrozole did not exhibit a major change in expression of oestrogen-regulated and proliferation-related genes, illustrating molecular resistance to treatment. The clinical relevance of these observations is that patients with ER-negative tumours should not be regarded as candidates for endocrine treatment. == Figure 1. == Changes in expression of oestrogen-regulated and proliferation-associated genes after 14 days of adjuvant treatment with letrozole. Green represents downregulation and red upregulation (these will show as relatively paler blocks if you are viewing this figure in black and white). Intensity of colour/shade represents degree of change. The single column to the left of the figure represents changes in an ER-negative case; the panels relate to 15 different clinically resistant ER-positive tumours: the left-hand panel illustrates a molecular resistant phenotype; the middle panel shows cases exhibiting decreases in the expression of oestrogen-regulated genes but not in cell cycle genes; and the right-hand panel shows molecular sensitivity in both oestrogen-regulated and cell cycle associated gene expression. ER, oestrogen receptor. However, many endocrine-resistant tumours have ER-positive phenotypes, and the challenge is FGH10019 to discriminate between ER-positive responsive and ER-positive resistant tumours, and to clarify the underlying cause of resistance in the latter. It is possible to envisage an aberrant receptor that may bind oestrogen or ER antibodies but not transduce a signal (RNAs encoding variant and mutant ER have been reported in breast cancer [9]). In this case, tumours would be inherently insensitive to hormone stimulation and refractory to endocrine deprivation therapy despite having ER-positive status. Another scenario is that ER is functional and driving oestrogen-dependent processes,.