The Cancer Research UK Cancer Therapeutics Unit, McElwain Laboratories, The Institute of Cancer Research, Sutton SM2 5NG, UK.
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
Int J Mol Sci. 2023 Jun 28;24(13):10757. doi: 10.3390/ijms241310757.
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.
人类胚胎乳腺发育的过程产生了乳腺细胞与皮肤上皮细胞（如角蛋白细胞）具有发育谱系关系的结构。由于先前已经表明一些乳腺癌表达高水平的角蛋白细胞分化标志物—— Involucrin，我们假设一些乳腺肿瘤可能会去分化为角蛋白细胞衍生的“进化史”。为了证实我们的假设，我们研究了 involucrin 的表达频率以及 Brk 的表达频率，Brk 是一种酪氨酸激酶，在高达 86%的乳腺癌中表达，其正常表达模式仅限于分化上皮细胞，尤其是皮肤（角蛋白细胞）和胃肠道。我们发现，角蛋白细胞分化标志物 involucrin 在很大比例（78%）的乳腺癌样本和细胞系中表达。有趣的是，发现表达高水平 involucrin 的肿瘤样本也表达 Brk。1,25-二羟维生素 D3 是一种已知的分化剂和潜在的抗癌剂，它降低了表达 involucrin 和 Brk 的乳腺癌细胞系的增殖，而测试的 Brk/involucrin 阴性细胞系则不太敏感。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。这些数据为越来越多的证据表明，细胞对 1,25-二羟维生素 D3 的反应可能独立于维生素 D 受体状态，并为潜在的标志物（如 Brk 和/或 involucrin）提供了深入了解，这些标志物可能预测对 1,25-二羟维生素 D3 的治疗反应。
