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Molecular aspects of early stages of breast cancer progression
1Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco 94115.
Abstract:
It is clear that breast cancer progression is associated with inactivation of a number of different recessive oncogenes. The most widely evaluated tumor suppressor gene, p53, is mutated in approximately 30-50% of sporadic breast cancers. Mutations usually occur early in malignant progression. Loss of heterozygosity (LOH) studies have identified numerous chromosomal regions where other recessive oncogenes relevant to breast cancer may be located. Each LOH is seen in a varying proportion of breast cancers and may appear either early or late in progression. High-grade ductal carcinoma in situ (DCIS) and invasive carcinoma have similar genetic lesions, showing that aberrations can occur before invasive disease. Direct evidence that the same aberrations can be acquired later in progression comes from a study of multiple metastases from the same patient; other studies found that primary invasive cancers are characterized by marked intratumor heterogeneity for each lesion examined. The model we propose to account for these results hypothesizes that multiple genetic lesions can accomplish each phenotype required for malignancy (i.e., dysregulated proliferation, invasion, angiogenesis, etc.) and that, for a given tumor, at least one aberrant gene for each phenotypic change is stochastically selected. Biological heterogeneity of breast cancer results from the stochastic acquisition of various genetic aberrations. We further propose that the lymphocytic reaction in high-grade DCIS may select for aggressive tumor subpopulations capable of escaping immune surveillance. Another aspect of tumor heterogeneity may be the multiple mechanisms employed by various tumors to escape immune surveillance.
Insights
Breast cancer progression involves inactivating tumor suppressor genes like p53. Tumor heterogeneity arises from the stochastic acquisition of genetic aberrations, leading to varied cancer development and immune evasion.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Breast cancer progression is linked to the inactivation of recessive oncogenes.
- The tumor suppressor gene p53 is frequently mutated in sporadic breast cancers, often early in malignant progression.
- Loss of heterozygosity (LOH) studies indicate other recessive oncogenes relevant to breast cancer may exist on various chromosomal regions.
Purpose of the Study:
- To propose a model explaining the genetic basis of breast cancer heterogeneity.
- To understand how genetic aberrations contribute to malignant phenotypes such as proliferation and invasion.
- To explore the role of immune surveillance in selecting for aggressive tumor subpopulations.
Main Methods:
- Analysis of genetic lesions in high-grade ductal carcinoma in situ (DCIS) and invasive breast carcinoma.
- Examination of genetic aberrations in multiple metastases from individual patients.
- Investigation of intratumor heterogeneity in primary invasive cancers.
Main Results:
- Genetic lesions in high-grade DCIS and invasive carcinoma are similar, suggesting early aberration acquisition.
- Aberrations can be acquired later in progression, as evidenced by studies of metastases.
- Primary invasive cancers exhibit significant intratumor heterogeneity for examined lesions.
Conclusions:
- Breast cancer heterogeneity results from the stochastic acquisition of genetic aberrations, with multiple lesions potentially driving each required malignant phenotype.
- The lymphocytic reaction in high-grade DCIS may promote the selection of aggressive tumor subpopulations that evade immune surveillance.
- Tumors employ diverse mechanisms to escape immune surveillance, contributing to overall tumor heterogeneity.