Mechanism Uncovered in Breast Cancer Drug Resistance

Some breast cancer tumors are not sensitive to Herceptin.

Researchers have identified how breast cancer tumors are able to resist chemotherapy drugs, and in a recent study were able to resensitize the tumors in patient biopsies and laboratory models.

In the study, researchers studied tumor biopsies collected from breast cancer patients, both before and after treatment with the go-to breast cancer drug trastuzumab (Herceptin). Some of the tumors were able to be treated with Herceptin, while others were not.

Researchers compared the activated genes in response tumors to those in non-responsive tumors. The results allowed researchers to uncover several genes that may help evade the drug.

Furthermore, when the gene S100P was blocked, it caused tumors previously resistant to Herceptin to become re-sensitized to the drug. The findings of the study were published in Oncotarget.

During the study, researchers investigated small pieces of genetic material called mRNAs and lincRNAs, which are created from DNA inside normal cells but become dysregulated in tumors. Initially, researchers identified 1542 mRNAs and 371 lincRNAs that were different between the tumor cells that were responsive to the Herceptin treatment and those that were non-responsive.

The differences were indicative that separate networks for cell signals were being activated in each group of tumor cells. The list of RNAs were narrowed down using cells grown in the laboratory, in order to find a RNA molecule that was therapeutically manipulated to disrupt signals in the tumor cells related to Herceptin-resistance.

“Our hypothesis was that there are gene expression differences in both mRNAs and lincRNAs between tumors from patients that respond to trastuzumab and tumors from patients that do not,” said lead researcher Ahmad Khalil, PhD.

To validate the findings from the tumor biopsies, researchers grew breast cancer tumor cells in their lab with HER2 on the surfaces. This is because Herceptin sticks to the HER2 protein found on the surfaces of 25% to 30% of early-stage breast cancer tumor cells, preventing it from activating, and controlling genes instead of breast cancer cells.

When the cells were exposed to Herceptin in a way that mimicked cancer treatment regimens, researchers found that some of the breast cancer cells became resistant to Herceptin after long-term exposure, like it had in tumors collected from patients. Researchers were able to identify mRNAs and lincRNAs that varied between Herceptin-resistant and Herceptin-sensitive HER2 cancer cells grown in the lab.

Next, researchers looked for any overlap between the list of different RNAs in tumor biopsies and in the laboratory-grown cancer cells. The research team was able to identify 18 mRNAs and 7 lincRNAs associated with Herceptin-resistance in both models.

One single gene in particular, S100P, stood out to researchers, and may be central to Herceptin-resistance after conducting additional laboratory experiments.

“S100P was one of the key genes that showed significant expression differences,” Khalil said. “It further stood out because it was part of a pathway that emerged from a separate set of computational analyses of large datasets.”

In breast cancer cells that are resistant to Herceptin, the gene S100P is highly activated compared with normal breast tissue. It belongs to a family of genes that work together to support tumor growth, and has been found in several compartments inside cancers cells.

Prior studies have associated S100P with pancreatic and prostate cancers. During the current study, researchers designed small pieces of genetic material that blocked S100P in breast cancer cells.

Researchers found that the lab-grown cells that were previously Herceptin-resistant became sensitive to the drug after exposure to S100P blockers. After further analyses, the findings indicated that S100P activates critical proteins inside breast cancer cells to compensate for those turned off when Herceptin blocks HER2.

This activation of proteins may help tumor cells adjust their gene expression in response to drugs in their environment.

“Our data demonstrated that high expression levels of S100P are required for cancer cells to become resistant to trastuzumab,” Khalil said.

The results from the study indicated that depleting S100P in breast cancer may be one way to resensitize tumors to Herceptin. Authors noted that the next step in the process will be to further investigate the resistance mechanism, and screen for drugs that could be used to block S100P in human tumors.

Furthermore, researchers also plan to investigate the role of other mRNAs and lincRNAs from their list in regulating resistance to Herceptin. Identifying the mechanism behind Herceptin-resistance has been challenging, but the current study is the first to find mechanisms present in both cells grown in the lab and tumors in patients with breast cancer.

For patients with early-stage breast cancer treated with Herceptin, approximately one-third relapse even if the drug was initially successful. The tumors in relapsed patients become resistant to Herceptin, which limits further treatment options.

“Trastuzumab is a first-line treatment for breast cancer patients with HER2 gene amplification,” Khalil said. “Thus, finding the mechanism of resistance to this major drug now opens the door to reverse the resistance, potentially curing many more patients.”