Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells

Veena Somasundaram, Sreelatha K. Hemalatha, Krishnendu Pal, Sutapa Sinha, Asha S. Nair, Debabrata Mukhopadhyay, Priya Srinivas

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Studies over the past decade and half have identified cancer stem cells (CSCs) to be responsible for tumorigenesis, invasion, sustenance of metastatic disease, radio- and chemo-resistance and tumor relapse. Recent reports have described the plasticity of breast CSCs (BCSCs) to shift between the epithelial and mesenchymal phenotypes via Epithelial-Mesenchymal Transition (EMT) and Mesenchymal-Epithelial Transition (MET) states as the reason for their invasive capabilities. Additionally, BRCA1 has been found to be a mammary stem cell fate determinant. However, it is not clear what would be the best marker that can be used for identifying CSCs in BRCA1 mutated cancers. Also, anticancer agents that can reduce CSC population in a BRCA1 defective condition have not been addressed so far. Methods: Putative BCSCs were identified based on Hoechst exclusion, CD44+/24-/low expression and Aldehyde Dehydrogenase 1 (ALDH1) positivity using flow cytometry. The 'stemness' of the isolated ALDH1+ cells were analysed by immunofluorescence, western blotting for stem cell and EMT markers as well as in vitro mammosphere assays. Induction of Reactive Oxygen Species (ROS) by Plumbagin (PB) in BCSCs was assayed by Dichloro-dihydro-fluorescein diacetate (DCF-DA) staining. Ovarian cancer xenografts treated with PB were subjected to immunohistochemical analysis to study the ability of PB to target CSCs. Results: We have confirmed that ALDH1 positivity is the best marker for the identification of BCSCs in BRCA1-defective breast cancer cell lines when compared to the CD marker profile and Side Population (SP) analysis. BRCA1 status was observed to be a determinant of the abundance of epithelial-like (ALDH1+) or mesenchymal-like (CD44+/24-/low) BCSCs, and the reconstitution of a full length, wild type BRCA1 in HCC1937 breast cancer cells possessing a mutated BRCA1, transforms them from 'stem-like' to more 'mesenchymal'. For the first time we have shown that Plumbagin (PB), a naturally occurring naphthoquinone which is predominantly a ROS inducer, could reduce BCSCs specifically in BRCA1-defective, basal-like cancer cells. Conclusions: The best marker for identifying BCSCs in BRCA1 defective condition could be ALDH1 and that BRCA1 mutated BCSCs would be mostly 'stem like' than 'mesenchymal'. Also ROS inducers like PB could reduce BCSCs in BRCA1 defective cancers.

Original languageEnglish (US)
Article number336
JournalBMC Cancer
Volume16
Issue number1
DOIs
StatePublished - May 26 2016

Fingerprint

Neoplastic Stem Cells
Breast
Breast Neoplasms
Epithelial-Mesenchymal Transition
Reactive Oxygen Species
Basal Cell Neoplasms
Stem Cells
Naphthoquinones
plumbagin
Neoplasms
Disease Resistance
Radio
Heterografts
Antineoplastic Agents
Ovarian Neoplasms
Population
Fluorescent Antibody Technique
Flow Cytometry
Carcinogenesis
Western Blotting

Keywords

  • ALDH1
  • BRCA1
  • Cancer stem cells
  • Plumbagin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Somasundaram, V., Hemalatha, S. K., Pal, K., Sinha, S., Nair, A. S., Mukhopadhyay, D., & Srinivas, P. (2016). Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells. BMC Cancer, 16(1), [336]. https://doi.org/10.1186/s12885-016-2372-4

Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells. / Somasundaram, Veena; Hemalatha, Sreelatha K.; Pal, Krishnendu; Sinha, Sutapa; Nair, Asha S.; Mukhopadhyay, Debabrata; Srinivas, Priya.

In: BMC Cancer, Vol. 16, No. 1, 336, 26.05.2016.

Research output: Contribution to journalArticle

Somasundaram, V, Hemalatha, SK, Pal, K, Sinha, S, Nair, AS, Mukhopadhyay, D & Srinivas, P 2016, 'Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells', BMC Cancer, vol. 16, no. 1, 336. https://doi.org/10.1186/s12885-016-2372-4
Somasundaram, Veena ; Hemalatha, Sreelatha K. ; Pal, Krishnendu ; Sinha, Sutapa ; Nair, Asha S. ; Mukhopadhyay, Debabrata ; Srinivas, Priya. / Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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