New target in the battle against breast cancer

Researchers are investigating the influence of cells in the microenvironment of breast cancer on tumor progression. Their study could contribute to the application of personalized chemotherapy.

By Washington Castilhos

Agência FAPESP – Breast cancer is one of the most heterogeneous tumors in terms of its physiological, cellular and molecular characteristics. Tumors are composed of a malignant epithelial component and the stroma, which comprises the extracellular matrix and adjacent mesenchymal stem cells, including fibroblasts, which constitute 20%-80% of the tumor mass.

The scientific literature provides evidence that stromal cells associated with tumors can influence a cancer’s behavior. Therefore, research focused on the molecular anatomy of the stroma—its association with breast cancer and its functional aspects and response to drugs—is the objective of a Thematic Project financed by FAPESP.

According to Professor Mitzi Brentani of the Universidade de São Paulo Medical School (FMUSP) who coordinates the research, focusing on the stroma is important because of its importance not only in the tumor invasion process but also in metastasis (when a new tumor forms from a previous one at a distant site).

The Thematic Project, which was started three years ago, involves researchers from the FMUSP Radiology Department of the A.C. Camargo Hospital, the Barretos Cancer Hospital, the Brazilian Institute for Cancer Control and Pérola Byington Hospital. The study could have a clinical impact on cancer treatment by identifying the ways in which stromal genes contribute to drug sensitivity.

The researchers initially verified that the cancerous fibroblasts had different genetic profiles than fibroblasts found in normal breast tissue obtained from patients undergoing mammoplasty for aesthetic reasons. They also found that one of the cancerous fibroblast characteristics is the expression of the protein S100A4, which is related to metastasis. As a result, the group initially studied the difference in genetic expression by sequencing fibroblasts obtained from different subtypes of breast tumors.

The researchers are attempting to answer a fundamental question: what changes in these fibroblasts parallel the loss of hormonal sensitivity in the corresponding tumor epithelial cells? The study continues with an evaluation of the microRNAs present in the fibroblasts.

“Many studies have been published on the antiproliferative and anti-inflammatory actions of vitamin D in breast cancer epithelial cells. We therefore became interested in the treatment of fibroblasts with vitamin D because we observed that they were a key factor in tumor development,” said Mitzi Brentani to Agência FAPESP. “We observed that vitamin D had an anti-inflammatory effect on the fibroblasts.”

The group also verified the action of rapamycin as an inhibitor of the pAKT/TOR pathway, which is a common proliferation pathway for this type of tumor.

“As the tumor is heterogeneous and composed of transformed epithelial cells and stroma, one of our goals was to verify whether chemotherapeutic agents aimed at diminishing the number of epithelial cells could also affect the stroma,” said Brentani.

Neoadjuvant therapy

In a previous study also funded by FAPESP, the group of researchers identified patterns of genetic expression in tumor epithelial cells that would allow tumors to be classified according to their response to chemotherapy.

To test the hypothesis that chemotherapeutic drugs could affect stromal cells, the researchers then applied neoadjuvant therapy—given before surgery to reduce the dimension of the tumor and allow for resection—using chemotherapeutic drugs.

The drugs used were doxorubicin, cyclophosphamide and paclitaxel—all proven tumor inhibitors. The objective was to correlate response to treatment with analyses of the fibroblast gene profile.

Brentani notes that this subproject, which includes some 70 patients from the Barretos Cancer Hospital, could lead to the identification of new therapeutic targets and help establish personalized chemotherapy based on predictors of response.

The researcher presented the study at the 6th Oncobiology Symposium held by the Medical Biochemistry Institute at the Universidade Federal do Rio de Janeiro at the end of September.