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Phenotypic heterogeneity drives differential disease outcome in a mouse model of triple negative breast cancer

Thankamony, AP and Ramkomuth, S and Ramesh, ST and Murali, R and Chakraborty, P and Karthikeyan, N and Varghese, BA and Jaikumar, VS and Jolly, MK and Swarbrick, A and Nair, R (2023) Phenotypic heterogeneity drives differential disease outcome in a mouse model of triple negative breast cancer. In: Frontiers in Oncology, 13 .

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Official URL: https://doi.org/10.3389/fonc.2023.1230647


The triple negative breast cancer (TNBC) subtype is one of the most aggressive forms of breast cancer that has poor clinical outcome and is an unmet clinical challenge. Accumulating evidence suggests that intratumoral heterogeneity or the presence of phenotypically distinct cell populations within a tumor play a crucial role in chemoresistance, tumor progression and metastasis. An increased understanding of the molecular regulators of intratumoral heterogeneity is crucial to the development of effective therapeutic strategies in TNBC. To this end, we used an unbiased approach to identify a molecular mediator of intratumoral heterogeneity in breast cancer by isolating two tumor cell populations (T1 and T2) from the 4T1 TNBC model. Phenotypic characterization revealed that the cells are different in terms of their morphology, proliferation and self-renewal ability in vitro as well as primary tumor formation and metastatic potential in vivo. Bioinformatic analysis followed by Kaplan Meier survival analysis in TNBC patients identified Metastasis associated colon cancer 1 (Macc1) as one of the top candidate genes mediating the aggressive phenotype in the T1 tumor cells. The role of Macc1 in regulating the proliferative phenotype was validated and taken forward in a therapeutic context with Lovastatin, a small molecule transcriptional inhibitor of Macc1 to target the T1 cell population. This study increases our understanding of the molecular underpinnings of intratumoral heterogeneity in breast cancer that is critical to improve the treatment of women currently living with the highly aggressive TNBC subtype. Copyright © 2023 Thankamony, Ramkomuth, Ramesh, Murali, Chakraborty, Karthikeyan, Varghese, Jaikumar, Jolly, Swarbrick and Nair.

Item Type: Journal Article
Publication: Frontiers in Oncology
Publisher: Frontiers Media SA
Additional Information: The copyright for this article belongs to the Authors.
Keywords: long untranslated RNA; mevinolin; small interfering RNA, angiogenesis; animal cell; animal experiment; animal model; animal tissue; Article; bioinformatics; cancer growth; cancer prognosis; cancer staging; carcinogenesis; carcinogenicity; cell population; cell proliferation; cell viability; clinical outcome; colony formation; controlled study; distant metastasis free survival; drug therapy; electroporation; female; flow cytometry; fluorescence activated cell sorting; gene expression; gene ontology; gene overexpression; genetic heterogeneity; genetic transcription; genetic transfection; high throughput sequencing; histopathology; human; human cell; in vitro study; in vivo study; metastasis free survival; microarray analysis; mouse; mouse model; MTT assay; nonhuman; overall survival; phenotype; protein expression; protein function; real time polymerase chain reaction; recurrence free survival; RNA isolation; RNA sequence; survival analysis; triple negative breast cancer; tumor associated leukocyte; tumor growth; tumor volume; upregulation; Western blotting
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 18 Dec 2023 03:07
Last Modified: 18 Dec 2023 03:07
URI: https://eprints.iisc.ac.in/id/eprint/83480

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