Department of Immunology, Genetics and Pathology, Uppsala University, 75237 Uppsala, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet, 14157 Stockholm, Sweden.
Int J Mol Med. 2018 Sep;42(3):1615-1624. doi: 10.3892/ijmm.2018.3737. Epub 2018 Jun 20.
Epidermal growth factor (EGF) and estrogen are potent regulators of breast tumorigenesis. Their short‑term actions on human breast epithelial cells have been investigated extensively. However, the consequence of a long‑term exposure to EGF and estrogen remains to be fully elucidated. The present study examined the effects of long‑term exposure to EGF and 17β‑estradiol on the proliferation, transformation, expression of markers of stemness, and tumorigenesis of MCF7 human breast adenocarcinoma cells. Exposure to EGF and/or 17β‑estradiol irreversibly enhanced the proliferation rate of MCF7 cells, even following withdrawal. However, in a mouse xenograft experiment, no significant difference in tumor volume was observed between tumors derived from cells exposed to EGF, 17β‑estradiol or EGF + 17β‑estradiol. Immunohistochemistry performed on tumors derived from 17β‑estradiol‑exposed cells revealed reduced cell proliferation and vessel scores, according to the results obtained using Ki67 and von Willebrand factor staining, respectively. The EGF‑ and/or 17β‑estradiol‑treated cells exhibited an increased ratio of cluster of differentiation (CD)44+/CD24‑ cells and enhanced ability to form mammospheres. Furthermore, the long‑term exposure of MCF7 cells to EGF and 17β‑estradiol altered their responsiveness to short‑term stimulatory or inhibitory treatments with EGF, 17β‑estradiol, transforming growth factor‑β1 (TGFβ1), Iressa and SB431542. Therefore, the findings indicated that sustained exposure of MCF7 cells to EGF and/or 17β‑estradiol resulted in enhanced cell proliferation and mammosphere formation, an increased ratio of CD44+/CD24‑ cells, and altered responses to short‑term treatments with EGF, 17β‑estradiol, TGFβ1, and drugs inhibiting these signaling pathways. However, this sustained exposure was not sufficient to affect tumor take or volume in a xenograft mouse model.
表皮生长因子（EGF）和雌激素是强有力的乳腺肿瘤发生调节剂。它们对人乳腺上皮细胞的短期作用已经被广泛研究。然而，长期暴露于 EGF 和雌激素的后果仍有待充分阐明。本研究探讨了长期暴露于 EGF 和 17β-雌二醇对 MCF7 人乳腺腺癌细胞增殖、转化、干性标志物表达和致瘤性的影响。EGF 和/或 17β-雌二醇的暴露不可逆地增强了 MCF7 细胞的增殖率，即使在撤药后也是如此。然而，在小鼠异种移植实验中，来自暴露于 EGF、17β-雌二醇或 EGF+17β-雌二醇的细胞的肿瘤体积没有显著差异。对 17β-雌二醇暴露细胞来源的肿瘤进行免疫组织化学染色显示，根据 Ki67 和 von Willebrand 因子染色的结果，细胞增殖和血管评分降低。EGF 和/或 17β-雌二醇处理的细胞表现出更高比例的 CD44+/CD24-细胞，并且增强形成乳腺球体的能力。此外，长期暴露于 EGF 和 17β-雌二醇的 MCF7 细胞改变了它们对 EGF、17β-雌二醇、转化生长因子-β1（TGFβ1）、Iressa 和 SB431542 的短期刺激或抑制治疗的反应性。因此，这些发现表明 MCF7 细胞持续暴露于 EGF 和/或 17β-雌二醇导致细胞增殖和乳腺球体形成增强、CD44+/CD24-细胞比例增加以及对 EGF、17β-雌二醇、TGFβ1 和抑制这些信号通路的药物的短期治疗反应性改变。然而，这种持续暴露不足以影响异种移植小鼠模型中的肿瘤摄取或体积。
