Anti-apoptotic proteins induce non-random genetic alterations that result in selecting breast cancer metastatic cells
Olga Méndez1, Yolanda Fernández, Miguel A Peinado
1Centre d' Oncologia Molecular, Institut de Recerca Oncológica-IDIBELL, Barcelona, Spain.
Abstract:
To shed light on the relationships between over-expression of anti-apoptotic proteins, genomic instability, and the metastatic ability of breast cancer cells, we analyzed genetic changes in tumors and metastases by orthotopically injecting MDA-MB 435 cells transfected with anti-apoptotic genes Bcl-xL or Bcl-2 into nude mice. Tumors and metastasis variants were extracted by primary culture from breast, bone, lung, and lymph node from mice with 435/Bcl-xL, 435/Bcl-2, and 435/Neo tumors. Using the Arbitrarily Primed Polymerase Chain Reaction (AP-PCR), which permits the detection of allelic imbalances, we generated four different fingerprints utilizing four primers. We found that the genetic damage fraction (GDF) increased in 435/Bcl-2 (GDF=0.55) and 435/Bcl-xL cells (GDF=0.34), in regard to 435/Neo control cells (GDF=0.29), indicating that non-random genetic alterations occurred in cells secondary to Bcl-2 or Bcl-xL over-expression. Anti-apoptotic proteins render breast cancer cells susceptible to the in vivo acquisition of highly tumorigenic (Kruskal-Wallis, P=0.019) and metastatic (Kruskal-Wallis, P=0.004) activity. We therefore propose that genetic instability is a molecular mechanism favored by anti-apoptotic proteins involved in the selection of highly metastatic cells during tumorigenesis, a pathogenic event favoring the expansion of metastasis.
Insights
Over-expressing anti-apoptotic proteins like Bcl-2 and Bcl-xL in breast cancer cells increases genomic instability. This genetic instability promotes the development of highly tumorigenic and metastatic cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Anti-apoptotic proteins play a role in cancer progression.
- Genomic instability is a hallmark of cancer.
- Breast cancer metastasis is a complex process.
Purpose of the Study:
- To investigate the link between anti-apoptotic protein over-expression, genomic instability, and metastatic potential in breast cancer.
- To determine if Bcl-2 and Bcl-xL influence genetic alterations and metastatic ability.
- To elucidate the molecular mechanisms driving breast cancer metastasis.
Main Methods:
- Orthotopic injection of MDA-MB 435 breast cancer cells (transfected with Bcl-xL, Bcl-2, or Neo control) into nude mice.
- Primary culture of tumors and metastases from various organs (breast, bone, lung, lymph node).
- Arbitrarily Primed Polymerase Chain Reaction (AP-PCR) to detect allelic imbalances and calculate the genetic damage fraction (GDF).
Main Results:
- Over-expression of Bcl-2 (GDF=0.55) and Bcl-xL (GDF=0.34) significantly increased the genetic damage fraction compared to Neo control cells (GDF=0.29).
- This indicates non-random genetic alterations occurred due to Bcl-2 or Bcl-xL over-expression.
- Anti-apoptotic proteins promoted the in vivo acquisition of highly tumorigenic (P=0.019) and metastatic (P=0.004) activity in breast cancer cells.
Conclusions:
- Genetic instability, favored by anti-apoptotic proteins, is a key mechanism in selecting for highly metastatic breast cancer cells.
- Anti-apoptotic proteins contribute to tumorigenesis by promoting genetic instability and subsequent metastatic expansion.
- Targeting anti-apoptotic pathways may offer strategies to inhibit breast cancer metastasis.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
02:21Cancers Originate from Somatic Mutations in a Single Cell
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:30Apoptosis