Yi Li Lab Research Projects

Estrogen receptor-positive (ER+) breast cancer comprises 70% of human breast cancer cases. Although there exist many mouse models of BCa, few are ER+ and none are estrogen-dependent.  Rat mammary glands resemble the human breast more closely than those of mice, and they readily form ER+ and estrogen-dependent tumors when treated with carcinogens or transduced with mutated Ras. Using intraductal injection of viruses to engineer genetic alterations directly somatic mammary cells in rats, we have developed multiple rat models of ER+ breast cancer, and several of them depend on estrogen for continued growth. These new models now offer unparalleled tools to investigate multiple critical questions in ER+ breast cancer research: 

1. What are the mechanisms controlling metastatic growth in bone versus visceral organs? 
2. What are the mechanisms of endocrine resistance? 
3. How are immune cells involved in metastatic progression? 
4. Why do ER+ breast cancer bone metastases present as immune-cold when they are immersed in an immune-rich bone microenvironment? 
5. Could ER+ bone metastases be converted to immune-hot and then treated with anti-immune checkpoint therapy?
   

Estrogen receptor-positive (ER+) breast cancer predominantly recurs in bone, often years and occasionally decades after surgical resection of the primary tumor and adjuvant endocrine therapy. Bone metastasis, once clinically detected, is incurable. Therefore, there is an urgent need to determine drivers of endocrine resistance and to identify factors contributing to the survival and outgrowth of disseminated tumor cells and micrometastases in the bone microenvironment. Members of the Bcl-2 anti-apoptotic family (Bcl-2, Bcl-xL, and Mcl1) are often upregulated in cancer cells to evade apoptosis and are associated with chemotherapy resistance in various human cancers. However, whether any member of this family is involved in breast cancer bone metastasis and therapeutic resistance remains unknown. The goal of this project is to investigate how Bcl-xL promotes ER+ breast cancer metastasis to bone and other organs, and how Bcl-xL contributes to resistance to endocrine therapy, and how we can pharmacologically block Bcl-xL to suppresses ER+ breast cancer progression and endocrine resistance.

Epidemiological studies have demonstrated that a first birth before age 25 lowers breast cancer risk, while a first birth after age 35 increases breast cancer risk. This age-dependent impact of first birth on breast cancer risk is generally attributed to the pregnancy itself, with much less consideration for the lactation that often ensues. In young women, evidence is strong that both pregnancy itself and lactation decrease breast cancer risk.  However, the relative contribution of pregnancy vs. lactation to increased breast cancer risk associated with a late-age reproduction has not been studied rigorously, either epidemiologically or experimentally. Lactation itself at any age is assumed to be beneficial to both mothers and infants, and is encouraged. However, our preliminary data suggest the hypothesis that lactation instigates preexistent early lesions to progress to cancer. Given the increasingly large population of women who choose to delay their first pregnancy to age 35 or older when the chance of having accumulated early lesions is heightened, our hypothesis, if proven, has important and immediate implications for these women and especially for women have been diagnosed with atypia. They can use this knowledge to make informed decisions regarding whether and how long they will breastfeed. The goal of this project is to rigorously test this hypothesis and study the underlying molecular mechanisms.