Karouji Kento, Tominari Tsukasa, Abe Reika, Sugasaki Moe, Ikeda Keisuke, Matsumoto Chiho, Miyaura Chisato, Miyata Shinji, Nomura Yoshihiro, Itoh Yoshifumi, Hirata Michiko, Inada Masaki
Cooperative Major in Advanced Health Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei-shi, Tokyo, 184-8588, Japan.
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei-shi, Tokyo, 184-8588, Japan.
Biochem Biophys Res Commun. 2025 Jan;742:151056. doi: 10.1016/j.bbrc.2024.151056. Epub 2024 Nov 27.
Patients with estrogen receptor alpha (ERα)-positive breast cancer are commonly treated with anti-estrogen drugs as an initial treatment strategy. Fulvestrant, an estrogen receptor antagonist, effectively blocks ERα signaling; however, long-term fulvestrant treatment induces drug resistance in the absence of ERα. In this study, we investigated the molecular mechanism underlying the loss of ERα, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ERα proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R. FOXO3a, a transcriptional regulator of ERα was decreased in Ful-R, and a ubiquitin-proteasome inhibitor restored the expression of FOXO3a. These results suggest that the suppression of FOXO3a and ERα led to the increased expression of TGF-α, EGFR, and HER2 and subsequent cell proliferation in Ful-R. This study highlights the potential development of therapeutic drugs targeting FOXO3a for the treatment of HER2-positive, estrogen, and progesterone receptor-negative her2-type proliferative breast cancers.
雌激素受体α（ERα）阳性乳腺癌患者通常采用抗雌激素药物作为初始治疗策略。氟维司群是一种雌激素受体拮抗剂，可有效阻断ERα信号传导；然而，长期使用氟维司群治疗会在缺乏ERα的情况下诱导耐药性。在本研究中，我们调查了氟维司群耐药性乳腺癌中ERα、FOXO3a缺失以及HER2诱导的分子机制。短期使用氟维司群治疗可通过泛素-蛋白酶体降解途径使MCF7细胞中的ERα蛋白降解。长期使用氟维司群治疗后，MCF7细胞转变为高增殖细胞（氟维司群耐药细胞：Ful-R）。这些细胞的雌激素和孕激素受体水平明显受到抑制。Ful-R中EGFR、HER2和ERK的磷酸化被诱导，这些磷酸化抑制剂可抑制Ful-R中的细胞增殖。ERα的转录调节因子FOXO3a在Ful-R中减少，泛素-蛋白酶体抑制剂可恢复FOXO3a的表达。这些结果表明，FOXO3a和ERα的抑制导致TGF-α、EGFR和HER2表达增加，随后Ful-R中的细胞增殖。本研究强调了针对FOXO3a开发治疗药物以治疗HER2阳性、雌激素和孕激素受体阴性her2型增殖性乳腺癌的潜在可能性。
