Breast tumors are frequently detected through physical palpation due to their apparent "hardness" compared to the soft normal mammary tissue. The "hardness" of breast tumors correlates with distant metastasis and poor outcome in breast cancer patients. Recent studies show that breast tumors show a 10- to 50-fold increase of mechanical force exerted on tumor cells compared to normal breast tissues and mechanical force generated by increasing hardness of breast tumors promotes breast cancer progression. However, it is unknown how mechanical force impacts breast cancer on the molecular level.

Chemotherapy is the main treatment regimen for aggressive and metastatic breast cancer. However, the development of chemoresistance is a hurdle that significantly hinders successful treatment outcomes. Cancer stem cells, a small population of cells in a breast tumor, are thought to be inherently more resistant to conventional cancer chemotherapies than the rest of rapidly proliferating tumor cells and responsible for tumor reoccurrence and metastasis. Only therapies that efficiently eliminate the cancer stem cell fraction of a tumor are thought to be able to induce long-term responses and thereby halt tumor progression. Currently, most studies on cancer stem cells mainly focus on the role of various biochemical signals in regulating breast cancer stem cell properties and function.

In this proposal, we hypothesize that the mechanical force generated by increasing hardness of breast tumors regulates breast cancer stem cell properties and function, therefore assisting breast tumor development and promoting chemoresistance. We combine cell and molecular biology techniques with new bioengineering research tools to access and manipulate mechanical force and the hardness of tumor tissue to make novel discoveries on the link between tissue stiffness, breast cancer stem cell, and chemoresistance. We propose this project under the Idea Award with Partnering Principal Investigator Option because the expertise in breast cancer biology (the Yang lab) and in bioengineering and stem cell biology (the Engler lab) is essential to implement this research program. Applying multidisciplinary approaches to breast cancer research is critical to address the role of tissue stiffness and mechanical force in breast cancer stem cell biology.

Given the critical role of breast cancer stem cells in breast tumor progression and chemoresistance, our research could lead to novel therapeutics targeting the mechanotransduction pathway to eradicate breast cancer stem cells and overcome chemoresistance. If successful, our research would address the unmet need of chemoresistance in breast cancer treatment.