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A Transposon-based Analysis Reveals RASA1 Is Involved in Triple-Negative Breast Cancer

Cristian Suárez-Cabrera1,2, Rita M Quintana1, Ana Bravo3

  • 1Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid, Spain.

Cancer Research
|January 22, 2017
PubMed

Insights

RAS pathway alterations are common in basal breast cancer. Loss of RAS GTPase-activating protein 1 (RASA1) contributes to malignant phenotypes, particularly in tumors with mutated p53.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • RAS pathway mutations are prevalent in human cancers but infrequent in breast cancer.
  • RAS GTPase-activating proteins (RASGAPs) negatively regulate RAS signaling.
  • RAS pathway dysregulation is implicated in tumorigenesis.

Purpose of the Study:

  • To investigate the role of RAS pathway negative regulators in breast cancer development.
  • To explore the potential involvement of RASGAP genes, neurofibromin1 (Nf1) and RAS p21 protein activator (Rasa1), in mammary tumorigenesis.

Main Methods:

  • Generated mammary tumors in a mouse model using a mutagenic transposon system in a p53 heterozygous background.
  • Analyzed transposon insertion sites in tumor DNA.
  • Performed immunohistochemical analysis on human breast tumors and bioinformatic analysis of The Cancer Genome Atlas (TCGA) data.
  • Inactivated RASA1 in MCF10A cells to assess its effect on cellular phenotype.

Main Results:

  • Mammary tumors in the mouse model frequently exhibited transposon insertions in Nf1 and Rasa1.
  • Low RASA1 expression was common in human basal (triple-negative) and estrogen receptor-negative breast tumors.
  • Bioinformatic analysis revealed frequent RASA1 allelic loss, especially in basal tumors and in conjunction with TP53 mutations.
  • RASA1 inactivation in MCF10A cells induced a malignant phenotype in the presence of mutated p53.

Conclusions:

  • Loss of negative RAS regulators, specifically RASA1, may be a frequent event in basal breast cancer.
  • Alterations in the Ras pathway due to RASA1 inactivation contribute to malignant transformation in breast cancer.
  • RASA1 deficiency represents a potential therapeutic target in a subset of breast cancers.

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