Improving Chemotherapy Against Aggressive Breast Cancers

Triple-negative breast cancer: study shows a way to improve treatment by weakening the extracellular matrix’s defense against chemotherapy.

Grantee: Ozgur Sahin, PhD
Institution: University of South Carolina
Area of Focus: Cell Structure and Metastasis
Grant Term: 1/1/2020 to 12/31/2023

“The extracellular matrix acts as a scaffolding around cells, giving them a supportive barrier. It’s a highly dynamic structure that’s constantly remodeled by cell and chemical changes. Normal cells make small amounts of this matrix, but tumor cells make large quantities of it, giving them a stronger barrier against anticancer drugs.
“My lab studies LOX, a well-known protein “remodeler” of the extracellular matrix. We found that blocking this protein seems to improve the effectiveness of chemotherapy against triple-negative breast cancer, making LOX a highly attractive therapeutic target for a new drug.” –Ozgur Sahin, PhD

The Challenge: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Though it accounts for 10% to 15% of all cases of breast cancer, it contributes to 30% of deaths from breast cancer.

Drug treatments (such as chemotherapy, immunotherapy, or targeted therapy) are often called "systemic" treatments because they affect the entire body. Unlike other subtypes of breast cancer, which can be treated with targeted therapies, the most effective treatment options for TNBC typically involve chemotherapy. But many TNBCs don’t respond completely to chemotherapy, or they stop responding to it (becoming “chemoresistant”), and that leaves cancer cells behind that can multiply and spread.

There’s a critical need to develop new ways to treat TNBC more effectively. To do this, researchers must find new aspects of the tumor cells to target.

The Research: American Cancer Society (ACS) grantee Ozgur Sahin, PhD, and his research lab team recently published a paper about their investigation of how to make TNBCs more responsive to chemotherapy treatments.

The researchers are focusing on a protein in the lysyl oxidase (LOX) family. These are proteins that some breast cancer tumor cells make high levels of to help keep the cancer cells alive even when oxygen levels are low (hypoxia).

Past research has well-established that LOX proteins help make tumors more aggressive by enhancing their ability to spread (metastasize). Research from Sahin and his team adds to the building evidence that higher levels of LOX proteins also make the tumors more resistant to chemotherapy.

LOX proteins create a matrix of fibers that surround the tumor and strengthen its barrier. This “extracellular matrix” can prevent drugs from reaching the tumor, while LOX and other proteins “turn down the volume” on messages that tell the cell when it’s time to die. Together, these actions help cancer cells live, grow, and spread (metastasize), moving from the where they started to distant parts of the body.

Studying human TNBC cells in lab dishes and in mice, Sahin and his team discovered that blocking the LOX protein helps stop this type of breast cancer’s growth and improves its response to chemotherapy by allowing anticancer drugs to:

  • More easily reach the tumor by decreasing the strength of the matrix fibers around the tumor and increasing drug penetration across the matrix.
  • More readily kill cancer cells by blocking communication pathways that keep cancer cells from dying—thus, reversing chemoresistance.

Why does it matter? Sahin’s team found that more than half of the people they studied with chemoresistant TNBC make high levels of LOX; and therefore, are expected to respond to LOX-targeting therapies used in combination with chemotherapy.

This finding and other results from Sahin’s research provide strong pre-clinical rationale for clinical trials in humans that develop and test new drugs to help overcome chemoresistance in people being treated for TNBC. In fact, his team is working to develop these new drugs now. These new therapeutics could include LOX-inhibitor drugs as well as drugs that would target and inhibit related communication pathways within the extracellular matrix.