Kurbel Sven
Department of Physiology, Osijek Medical Faculty, J. Huttlera 4, 31000 Osijek, Croatia.
Med Hypotheses. 2005;64(6):1182-7. doi: 10.1016/j.mehy.2004.09.026.
Reports that selective estrogen receptor modulators (SERMs) reduce occurrence of only estrogen receptor (ER) positive tumors strongly support the etiological distinction between ER positive and ER negative breast cancers. Based on these evidences three concepts are described: Concept I. The occurrence of ER negative tumor cells might be a consequence of the clonal selection among tumor cells. This would lead to mosaicism in the ER expression. If ER negative cells become the most prevalent clone, the patient will be diagnosed to have an ER negative breast cancer. Since all cancers start as ER positive, SERMs should equally prevent occurrence of ER positive and ER negative breast cancers, but this prediction is evidently wrong. Concept II. Mammary ducts normally contain ER positive and ER negative cells, both prone to malignancy. Cancer occurrence in ductal cells that normally lack ER would be unrelated to estrogen exposure or SERMs protection. Estrogen and SERMs can influence cancer occurrence only in ER positive ductal cells. The main drawback is that this concept does not predict occurrence of mosaicism in ER expression among tumor cells. Unified Concept I and II. To overcome limitations of described concept a unified concept is presented. Cancers from ER positive ductal cells start as pure ER positive tumors and those from ER negative ductal cells as pure ER negative tumors. During the preclinical phase, in some ER positive tumors, clonal selection introduces ER negative clones. These tumors become mosaic in the cellular ER expression, some of them predominantly ER positive other ER negative. Estrogen deprivation, or SERMs can help mostly to patients with pure ER positive, or mosaic ER positive tumors. Since the dominant metastatic clone can have different ER status from the primary breast tumor, both surprising successes and failures of endocrine therapy can be expected in tumors with mosaic ER expression.
有报道称，选择性雌激素受体调节剂（SERM）仅能降低雌激素受体（ER）阳性肿瘤的发生率，这有力地支持了ER阳性和ER阴性乳腺癌在病因学上的区别。基于这些证据，描述了三个概念：概念I。ER阴性肿瘤细胞的出现可能是肿瘤细胞间克隆选择的结果。这将导致ER表达的镶嵌现象。如果ER阴性细胞成为最普遍的克隆，患者将被诊断为患有ER阴性乳腺癌。由于所有癌症最初都是ER阳性的，SERM应该同样能预防ER阳性和ER阴性乳腺癌的发生，但这一预测显然是错误的。概念II。乳腺导管通常含有ER阳性和ER阴性细胞，两者都易于发生恶性肿瘤。正常情况下缺乏ER的导管细胞发生癌症与雌激素暴露或SERM保护无关。雌激素和SERM只能影响ER阳性导管细胞中的癌症发生。主要缺点是，这个概念无法预测肿瘤细胞中ER表达的镶嵌现象。统一概念I和II。为了克服上述概念的局限性，提出了一个统一的概念。来自ER阳性导管细胞的癌症最初是纯ER阳性肿瘤，而来自ER阴性导管细胞的癌症则是纯ER阴性肿瘤。在临床前阶段，在一些ER阳性肿瘤中，克隆选择引入了ER阴性克隆。这些肿瘤在细胞ER表达上变得镶嵌，其中一些主要是ER阳性，另一些是ER阴性。雌激素剥夺或SERM主要对纯ER阳性或ER阳性镶嵌的肿瘤患者有帮助。由于主要的转移克隆可能与原发性乳腺肿瘤有不同的ER状态，因此在ER表达镶嵌的肿瘤中，内分泌治疗可能会出现令人惊讶的成功和失败。
