Shokrollahi Barough Mahdieh, Jalili Neda, Shafiee Soodabe, Salehi Malihe, Naseri Nazanin, Javidi Mohammad Amin, Hosseinzadeh Aysooda, Farahmand Leila
ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran 1517964311, Iran; Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran; Department of Immunology, Iran University of Medical Sciences, Tehran 1449614535, Iran.
Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
Int Immunopharmacol. 2023 Nov;124(Pt A):110792. doi: 10.1016/j.intimp.2023.110792. Epub 2023 Aug 24.
One of the most pressing concerns associated with breast cancer-targeted therapies is resistance to Tamoxifen and Herceptin. Such drug resistance is usually characterized by reduced expression of certain cell surface receptors. Some biological regimens can induce perceptible overexpression of these receptors in favor of drug responsiveness.
In this research, drug-responsive MCF-7 and SKBR-3, along with drug-resistant MCF-7R (Tamoxifen resistant) and JIMT-1 (Herceptin resistant) breast cancer cell lines in 2D and 3D cultures were exposed to anti-MUC1 nanobody and then assessed for their ER, PR, and HER2 gene and protein expression using qRT-PCR and immunofluorescent staining analyses. Cell viability and the synergistic relationships of combination treatments were determined with MTT assay followed by CompuSyn software. Apoptotic cells were evaluated with Annexin V/propidium Iodide (PI) and acridine orange/ethidium bromide (AO/EB) staining.
Anti-MUC1 exposure elevated the expression levels of ER (42 folds), PR (18.5 folds), and HER2 (4.7 folds). As a result of co-treatment, the IC levels for Tamoxifen and Herceptin were reduced by up to 10 and 3 folds, respectively. MCF-7R cells responded positively to Tamoxifen, as evidenced by a 5-fold reduction in the IC and enhanced apoptosis.
The ER, PR, and HER2 overexpression after MUC1 blocking could signal drug hypersensitization and facilitate drug resistance management.
与乳腺癌靶向治疗相关的最紧迫问题之一是对他莫昔芬和赫赛汀的耐药性。这种耐药性通常表现为某些细胞表面受体的表达降低。一些生物疗法可以诱导这些受体明显过表达，从而有利于药物反应性。
在本研究中，将二维和三维培养的对药物敏感的MCF-7和SKBR-3，以及耐药的MCF-7R（对他莫昔芬耐药）和JIMT-1（对赫赛汀耐药）乳腺癌细胞系暴露于抗MUC1纳米抗体，然后使用qRT-PCR和免疫荧光染色分析评估其雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子受体2（HER2）基因及蛋白表达。通过MTT法及CompuSyn软件测定细胞活力和联合治疗的协同关系。用膜联蛋白V/碘化丙啶（PI）和吖啶橙/溴化乙锭（AO/EB）染色评估凋亡细胞。
暴露于抗MUC1后，ER（42倍）、PR（18.5倍）和HER2（4.7倍）的表达水平升高。联合治疗的结果是，他莫昔芬和赫赛汀的半数抑制浓度（IC）水平分别降低了多达10倍和3倍。MCF-7R细胞对他莫昔芬有阳性反应，IC降低5倍并增强凋亡证明了这一点。
MUC1阻断后ER、PR和HER2的过表达可能预示着药物超敏反应，并有助于耐药性的管理。
