The role of AMPK and CD36 in breast cancer metastasis

Jesse Brown Va Medical Center, Chicago IL

Investigators

Linked publications, trials & patents

Abstract

Background and Innovation: The mortality and morbidity from breast cancer are due to its metastatic spread. Clinical data showed a strong correlation between the expression of fatty acids translocase CD36 and the progression of breast cancer and tumor-free survival. We found in mouse models of breast cancer metastasis that high fat diet (HFD) increased metastasis and either cell autonomous deletion or systemic deletion of CD36, which emulates drug therapy, inhibits HFD-induced metastasis. Since the systemic deletion of CD36 does not exert any adverse consequences, the results suggest that it is a therapeutic target for breast cancer metastasis. We also discovered a new paradigm and showed that CD36 is not an unbiased transporter of fatty acids but enables the uptake of saturated fatty acids by increasing the uptake of unsaturated fatty acids to prevent lipotoxicity. Finally, we found that the induction of CD36 expression is dependent on the activation of AMPK. The role of AMPK in tumorigenesis is controversial. Although AMPK inhibition was implicated in promoting tumorigenesis, we and others showed, that AMPK activation is required for tumor cells survival during tumor formation and its inhibition impedes tumor growth. We found that AMPK is also required for breast cancer metastasis in several mouse models of breast cancer metastasis, and that expression of CD36, inhibition of oxidative stress, and the inhibition of the downstream effector of AMPK, acetyl-CoA carboxylase (ACC) could recover metastasis inhibited by AMPK deletion. In this grant application we will further delineate the mechanisms by which AMPK and CD36 are required for metastasis. In the first part of the grant application, we will determine the time during tumor development in which AMPK is required for metastasis; we will explore the roles of ACC1 and ACC2 downstream of AMPK in mediating metastasis; and we will determine the effect of AMPK activation, which is considered anti-tumorigenic, on breast cancer metastasis. In the second part of the grant application, we will delineate the mechanisms by which CD36 is required for breast cancer metastasis downstream of AMPK and we will explore the effect of systemic CD36 deletion on tumor microenvironment. We will employ patient derived xenografts (PDXs) and patient derived organoids (PDOs) to determine the effect of AMPK activation on tumor growth and metastasis as well as the effect of CD36 inhibition on tumor growth and metastasis. In summary, will use human breast cancer cell lines and patients derived organoids and orthotopic transplantation as well as genetically engineered mouse models for breast cancer metastasis in these studies. Significance and Impact to Veterans Healthcare: Breast cancer is the most frequently occurring cancer in women. Military women are at increased risk of metastatic breast cancer. There is a gap in knowledge whether breast cancer patients should be treated with AMPK activators or anti-CD36. Path to translation/implementation: The proposed studies have a translational impact as they will determine whether drug therapy that activates AMPK directly or indirectly could have worse outcomes with respect to breast cancer metastasis, and whether targeting CD36 could inhibit breast cancer metastasis particularly in obese patients.