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

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

Natalia Vargas-Rondón  1 , Erika Pérez-Mora  1 , Victoria E Villegas  2 , Milena Rondón-Lagos  1
Affiliations

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

Natalia Vargas-Rondón et al. Cancer Biol Med. .

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 in situ 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.

Keywords: Breast cancer; FISH; chromosomal instability; clonal heterogeneity; therapy resistance.

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Conflict of interest statement

Conflicts of interest statement No potential conflicts of interest are disclosed.

Figures

Figure 1
Figure 1
CIN and SDI in untreated BC cell lines. The level of CIN and the SDI (indicative of CH) in the five cell lines is color coded according to the legend at the bottom.
Figure 2
Figure 2
Effects of tamoxifen (TAM), docetaxel (DOC), doxorubicin (DOX), TAM+DOC and TAM+DOX treatments for 24 h, 48 h, and 96 h on cell proliferation in (A, B) MCF7 cells, (C, D) ZR751 cells and (E, F) MDA-MB468 cells. Error bars represent mean standard deviation of 24 replicates.
Figure 3
Figure 3
CIN and SDI (indicative of CH) in HER2- BC cells treated with tamoxifen (TAM), docetaxel (DOC), doxorubicin (DOX), TAM+DOC and TAM+DOX at various time points. The level of CIN and the SDI before and after treatments in ERa+/PR+/HER2− cells (MCF7 and ZR751) and ERa−/PR−/HER2− cells (MDA-MB468) is color coded according to the legend at the bottom.
Figure 4
Figure 4
Representative FISH images of the MCF7 BC cells after (A) DOC treatment and (B) TAM+DOX treatment. Three-color FISH was performed on nuclei spreads for chromosomes 2, 8 and 11 and, chromosomes 3, 15 and 17 using centromeric probes (CEP) labeled with different spectrum colors: spectrum orange for CEP2 and CEP3; spectrum aqua for CEP8 and CEP17; and spectrum green for CEP11 and CEP15. Interphase nuclei at each treatment time point are indicated. Ctrl: Control, untreated cells.
Figure 5
Figure 5
Representative FISH images of the MDA-MB468 BC cells after (A) TAM+DOC treatment and (B) DOX treatment. Three-color FISH was performed on nuclei spreads for chromosomes 2, 8 and 11 and, chromosomes 3, 15 and 17 using centromeric probes (CEP) labeled with different spectrum colors: spectrum orange for CEP2 and CEP3; spectrum aqua for CEP8 and CEP17; and spectrum green for CEP11 and CEP15. Interphase nuclei at each treatment time point are indicated. Ctrl: Control, untreated cells.
Figure 6
Figure 6
Effects of tamoxifen (TAM), docetaxel (DOC), doxorubicin (DOX), herceptin (HT), TAM+DOC, TAM+DOX, TAM+HT, HT+DOC and HT+DOX treatments for 24 h, 48 h, and 96 h on proliferation in (A, B) BT474 cells and (C, D) KPL4 cells. Error bars represent mean standard deviation of 24 replicates.
Figure 7
Figure 7
CIN and SDI (indicative of CH) induced by tamoxifen (TAM), docetaxel (DOC), doxorubicin (DOX), Herceptin (HT), TAM+DOC, TAM+DOX, TAM+HT, HT+DOC and HT+DOX in HER2+ BC cells at each treatment time point. The level of CIN and the SDI before and after treatments in ER+/PR+/HER2+ cells (BT474) and ER−/PR−/HER2+ cells (KPL4) is color coded according to the legend at the bottom.
Figure 8
Figure 8
CIN threshold at which cells are sensitive or resistant to treatments.
See this image and copyright information in PMC

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