Project

DAPI stain of human breast cancer cells (in pink) that have been grafted onto mouse tissue.

Breast Cancer Genomics

Sequencing aggressive breast cancers

Breast cancer has become one of the more well-characterized cancers, particularly from a molecular and genetic standpoint. Thanks to a number of in-depth genetic analyses, the disease has been classified into four distinct sub-types, including luminal A, luminal B, basal-like, and Her2-positive. Researchers at the McDonnell Genome Institute are focusing on the sequencing and analysis of basal-like tumors, which are among the most aggressive breast tumors.

Breast Cancer Genomics Details

Four Sub-Types

Breast cancer occurs due to changes in the DNA of breast tissue that cause certain cells to grow unchecked and form tumors. There are many different types of breast cancer and each one may have a different treatment and prognosis. Breast cancer has become one of the more well-characterized cancers, particularly from a molecular and genetic standpoint. Thanks to a number of in-depth genetic analyses, the disease has been classified into four sub-types:

  • Luminal A and luminal B: These are the two most common sub-types of breast cancer. They tend to be less aggressive and progress more slowly. These sub-types are known as estrogen receptor (ER)-positive, since they contain estrogen receptors that bind to the hormone estrogen, which helps the tumor cells grow. Luminal A cancers have the best outcomes, while luminal B cancers grow slightly faster than luminal A and have a slightly less positive outcome.

  • HER2-positive: This sub-type of cancer contains a protein called human epidermal growth factor receptor 2 (HER2), that causes the cancer cells to grow. This type of cancer tends to grow more quickly and may have a poor outcome, though it can often be treated successfully with drugs such as Herceptin, which targets the HER2 protein to prevent cell growth.

  • Basal-like: This sub-type of cancer is also known as 'triple-negative', meaning its cells have no estrogen or progesterone hormone receptors and have normal amounts of HER2. This type of cancer is more common in women who carry a mutation in their BRCA1 gene and in younger and African-American women. These cancers tend to grow quickly, don’t respond as well to many of the available treatments and have poor outcomes.

Tailoring Therapies

Classifying breast cancer into these sub-types is helping researchers tailor therapies and treatments to each individual case. It is also providing a better understanding of key genes that are mutated or otherwise altered in each patient’s genomic DNA. A study led by researchers at the McDonnell Genome Institute is working toward these goals. The work involved sequencing and analyzing tumors from a basal-like subtype 44-year-old female African American breast cancer patient. The scientists took DNA samples from the patient’s basal-like tumor cells and her normal cells. Using specially developed analysis approaches, they searched for and worked on characterizing all of the human genes that were changed or mutated in the tumor genome, as well as identifying all large-scale structural changes to the genome (such as genes that are deleted or that have moved around the chromosomes).

In this study of a basal-like subtype tumor, the researchers also looked at the genome of the metastatic tumor that had moved to the patient’s brain 8 months after her initial diagnosis. Most patients tend to die from their metastatic disease, which can develop at a distant location from the initial tumor, often after treatment for the primary disease. The researchers are now studying additional basal-like breast tumors with a long-term goal of better understanding the changes in the genome of the primary tumor and seeing how they compare to or affect the metastatic tumor. They are trying to identify the genetic signatures of the metastatic cancer in the hopes of predicting where it will move to, how often it might occur and for use as potential targets in the treatment of this form of cancer.

Ongoing Breast Cancer Trial

The scientists are also sequencing the genomes of patients in another ongoing study – trial Z1031, led by the American College of Surgeons Oncology Group (ACOSOG) – that is examining the response of women with estrogen-receptor (ER)-positive breast cancer to a class of chemotherapy drugs called “aromatase inhibitors.” ER positive disease is the most common form of breast cancer, occurring in about 65-70% of cases. The tumor cells in this form of cancer carry estrogen receptors on their surface and grow in response to the estrogen hormone. The women in this study are receiving one of three aromatase inhibitor drugs, which deprive the tumor cells of estrogen so they will stop growing. The idea overall is to shrink the tumors so that patients can undergo breast-conserving surgery rather than a radical mastectomy that removes the entire breast. For some still unknown reason, certain patients' tumors do not respond to the aromatase inhibitors and their cancer cells do not stop growing. For this reason, the researchers are trying to come up with a genomic profile that predicts how a given patient will (or won't) respond to these drugs.

This kind of genomic profiling could eventually determine with improved accuracy which patient will respond to aromatase inhibitor drugs versus which ones will require either a more conservative drug treatment or a targeted therapy approach that takes into account the mutations present in the tumor.

Funding for this work is provided by the National Human Genome Research Institute (NHGRI) and the Washington University Cancer Genome Initiative.