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Identification and mechanisms of endocrine resistance

DOI: 10.1186/bcr2179

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Abstract:

Endocrine resistance may be subdivided into the following types: primary or de novo, and secondary or acquired (occurring after an initial response to treatment). The term 'acquired' infers that, under the pressures of treatment, inductive molecular changes or clonal selection occurs, resulting in a resistant cellular phenotype with an independent growth advantage. Adaptive changes in key molecules of signalling pathways have been observed with endocrine treatment, such as loss of oestrogen receptors (ERs) and over-expression of c-erbB2 at relapse on tamoxifen [1]. Under these circumstances, the underlying mechanisms of resistance might be expected to be common to primary and secondary types.Endocrine resistance is most often thought of in clinical terms, but resistance may also occur at pathological, proliferative and molecular levels. Although these parameters are positively correlated, they are 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 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.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 ne

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