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染色体不稳定性和克隆异质性在乳腺癌细胞系治疗反应中的作用。

Role of chromosomal instability and clonal heterogeneity in the therapy response of breast cancer cell lines.

机构信息

School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja 150003, Colombia.

Biology Program, Faculty of Natural Sciences, Universidad del Rosario, Bogotá 111221, Colombia.

出版信息

Cancer Biol Med. 2020 Nov 15;17(4):970-985. doi: 10.20892/j.issn.2095-3941.2020.0028. Epub 2020 Dec 15.

DOI:10.20892/j.issn.2095-3941.2020.0028
PMID:33299647
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7721098/
Abstract

OBJECTIVE

Chromosomal instability (CIN) is a hallmark of cancer characterized by cell-to-cell variability in the number or structure of chromosomes, frequently observed in cancer cell populations and is associated with poor prognosis, metastasis, and therapeutic resistance. Breast cancer (BC) is characterized by unstable karyotypes and recent reports have indicated that CIN may influence the response of BC to chemotherapy regimens. However, paradoxical associations between extreme CIN and improved outcome have been observed.

METHODS

This study aimed to 1) evaluate CIN levels and clonal heterogeneity (CH) in MCF7, ZR-751, MDA-MB468, BT474, and KPL4 BC cells treated with low doses of tamoxifen (TAM), docetaxel (DOC), doxorubicin (DOX), Herceptin (HT), and combined treatments (TAM/DOC, TAM/DOX, TAM/HT, HT/DOC, and HT/DOX) by using fluorescence hybridization (FISH), and 2) examine the association with response to treatments by comparing FISH results with cell proliferation.

RESULTS

Intermediate CIN was linked to drug sensitivity according to three characteristics: estrogen receptor α (ERα) and HER2 status, pre-existing CIN level in cancer cells, and the CIN induced by the treatments. ERα+/HER2 cells with intermediate CIN were sensitive to treatment with taxanes (DOC) and anthracyclines (DOX), while ERα/HER2, ERα+/HER2+, and ERα-/HER2+ cells with intermediate CIN were resistant to these treatments.

CONCLUSIONS

A greater understanding of CIN and CH in BC could assist in the optimization of existing therapeutic regimens and/or in supporting new strategies to improve cancer outcomes.

摘要

目的

染色体不稳定性（CIN）是癌症的一个标志，其特征是细胞间染色体数量或结构的变化，在癌细胞群体中经常观察到，与预后不良、转移和治疗耐药性有关。乳腺癌（BC）的特点是不稳定的核型，最近的报告表明 CIN 可能影响 BC 对化疗方案的反应。然而，在极端 CIN 和改善结果之间观察到了矛盾的关联。

方法

本研究旨在 1）通过荧光杂交（FISH）评估 MCF7、ZR-751、MDA-MB468、BT474 和 KPL4 BC 细胞在低剂量他莫昔芬（TAM）、多西紫杉醇（DOC）、阿霉素（DOX）、赫赛汀（HT）和联合治疗（TAM/DOC、TAM/DOX、TAM/HT、HT/DOC 和 HT/DOX）下的 CIN 水平和克隆异质性（CH），2）通过比较 FISH 结果与细胞增殖，研究与治疗反应的相关性。

结果

根据三种特征，中等 CIN 与药物敏感性相关：雌激素受体 α（ERα）和 HER2 状态、癌细胞中预先存在的 CIN 水平以及治疗引起的 CIN。中等 CIN 的 ERα+/HER2 细胞对紫杉烷（DOC）和蒽环类药物（DOX）敏感，而中等 CIN 的 ERα/HER2、ERα+/HER2+和 ERα-/HER2+细胞对这些治疗耐药。

结论

对 BC 中的 CIN 和 CH 有更深入的了解，可以帮助优化现有的治疗方案，或支持改善癌症结果的新策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/771f/7721098/ac8995040e11/cbm-17-970-g008.jpg
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