Dataset Information

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

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 ? (ER?) and HER2 status, pre-existing CIN level in cancer cells, and the CIN induced by the treatments. ER?+/HER2- cells with intermediate CIN were sensitive to treatment with taxanes (DOC) and anthracyclines (DOX), while ER?-/HER2-, ER?+/HER2+, and ER?-/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.

SUBMITTER: Vargas-Rondon N

PROVIDER: S-EPMC7721098 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Vargas-Rondón Natalia N Pérez-Mora Erika E Villegas Victoria E VE Rondón-Lagos Milena M

Cancer biology & medicine 20201101 4

<h4>Objective</h4>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 an ...[more]

PMID: 33299647

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Project description:BACKGROUND:Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in molecular and phenotypic heterogeneity within the tumor, the complexity of which is further amplified through specific interactions between cancer cells. We aimed to dissect the molecular mechanisms underlying the cooperation between different clones. METHODS:We produced clonal cell lines derived from the MDA-MB-231 breast cancer cell line, using the UbC-StarTrack system, which allowed tracking of multiple clones by color: GFP C3, mKO E10 and Sapphire D7. Characterization of these clones was performed by growth rate, cell metabolic activity, wound healing, invasion assays and genetic and epigenetic arrays. Tumorigenicity was tested by orthotopic and intravenous injections. Clonal cooperation was evaluated by medium complementation, co-culture and co-injection assays. RESULTS:Characterization of these clones in vitro revealed clear genetic and epigenetic differences that affected growth rate, cell metabolic activity, morphology and cytokine expression among cell lines. In vivo, all clonal cell lines were able to form tumors; however, injection of an equal mix of the different clones led to tumors with very few mKO E10 cells. Additionally, the mKO E10 clonal cell line showed a significant inability to form lung metastases. These results confirm that even in stable cell lines heterogeneity is present. In vitro, the complementation of growth medium with medium or exosomes from parental or clonal cell lines increased the growth rate of the other clones. Complementation assays, co-growth and co-injection of mKO E10 and GFP C3 clonal cell lines increased the efficiency of invasion and migration. CONCLUSIONS:These findings support a model where interplay between clones confers aggressiveness, and which may allow identification of the factors involved in cellular communication that could play a role in clonal cooperation and thus represent new targets for preventing tumor progression.

Dataset Information

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

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

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