人胚胎乳腺发育的过程产生了其中乳腺细胞与皮肤上皮细胞如角质形成细胞共享发育谱系的结构。由于一些乳腺癌先前已被证明表达高水平的总蛋白,角质形成细胞分化的标志物,我们假设某些乳腺肿瘤可能去分化为角质形成细胞衍生的“进化史”。为了证实我们的假设,我们调查了总蛋白的表达频率以及Brk的表达频率,酪氨酸激酶在高达86%的乳腺癌中表达,其正常表达模式仅限于分化的上皮细胞,最值得注意的是皮肤(角质形成细胞)和胃肠道。我们发现总蛋白,角质形成细胞分化标记,在高比例(78%)的乳腺癌样品和细胞系中表达。有趣的是,发现表达高水平的总蛋白的肿瘤样品也显示表达Brk。1,25-二羟维生素D3,一种已知的分化剂和潜在的抗癌剂,在同时表达总蛋白和Brk的乳腺癌细胞系中增殖减少,而测试的Brk/incoucrin阴性细胞系较不敏感。此外,对1,25-二羟维生素D3的反应与维生素D受体表达无关.这些数据有助于越来越多的证据表明,细胞对1,25-二羟维生素D3的反应可能与维生素D受体状态无关,并提供了对潜在标志物的见解。例如可以预测对1,25-二羟基维生素D3的治疗反应的Brk和/或incovenucrin。
The process of human embryonic mammary development gives rise to the structures in which mammary cells share a developmental lineage with skin epithelial cells such as keratinocytes. As some breast carcinomas have previously been shown to express high levels of
involucrin, a marker of keratinocyte differentiation, we hypothesised that some breast tumours may de-differentiate to a keratinocyte-derived \'evolutionary history\'. To confirm our hypothesis, we investigated the frequency of
involucrin expression along with that of Brk, a tyrosine kinase expressed in up to 86% of breast carcinomas whose normal expression patterns are restricted to differentiating epithelial cells, most notably those in the skin (keratinocytes) and the gastrointestinal tract. We found that
involucrin, a keratinocyte differentiation marker, was expressed in a high proportion (78%) of breast carcinoma samples and cell lines. Interestingly, tumour samples found to express high levels of
involucrin were also shown to express Brk. 1,25-dihydroxyvitamin D3, a known differentiation agent and potential anti-cancer agent, decreased proliferation in the breast cancer cell lines that expressed both involucrin and Brk, whereas the Brk/
involucrin negative cell lines tested were less susceptible. In addition, responses to 1,25-dihydroxyvitamin D3 were not correlated with vitamin D receptor expression. These data contribute to the growing body of evidence suggesting that cellular responses to 1,25-dihydroxyvitamin D3 are potentially independent of vitamin D receptor status and provide an insight into potential markers, such as Brk and/or involucrin that could predict therapeutic responses to 1,25-dihydroxyvitamin D3.