Understanding the roles of lysyl oxidases in breast cancer metastasis and invasion
In 2013, it is estimated that 296,000 women in the U.S.A. will be diagnosed with breast cancer. Among those who are diagnosed before their cancer has started to spread, 99% will still be living 5 years after their diagnosis. However, for women who have progressed to distant-stage/metastatic breast cancer (i.e. cancer that has spread to other parts of the body), the 5-year survival rate plunges to ~24%; these women will account for the vast majority of the expected 40,000 breast cancer deaths in 2013. The dramatic decline in survival rate highlights the critical need to answer two pressing questions:
- What are the molecular mechanisms that drive the progression of breast cancer from a localized tumor (i.e non-invasive) to a raging horde of invasive cancer cells?
- How can progression of the metastatic potential/invasiveness of tumor cells be slowed, stopped, or even reversed?
In recent years, lysyl oxidase (LOX) and lysyl oxidase-like 2 (LOXL2) have been identified as contributors to increased breast cancer invasion/metastasis. These two proteins are Cu2+- and lysine tyrosylquinone cofactor-dependent amine oxidases. Traditionally, LOX has been known for its role in promoting the crosslinking of collagen and elastin, thereby facilitating construction of the extracellular matrix. This activity is essential to normal tissue development and wound healing. However, over-expression of LOX and LOXL2 is associated with increased invasiveness of breast cancer cells, and generally indicates a poor outlook for breast cancer patients.
How do LOX and LOXL2 contribute to cancer metastasis/invasion, and how could their actions be inhibited? We are currently applying a combination of techniques (e.g. bioorganic chemistry, biochemistry, bioanalytical chemistry, molecular cell biology, molecular imaging, and in vivo studies) to unveil the exciting and surprising answer(s) to these questions. Ultimately, we hope that these answers will guide the rational design of specific inhibitors (i.e. therapeutic drugs) that could be used to combat metastatic cancers.