Abstract
Tamoxifen inhibits estrogen receptor (ER)-positive breast cancer growth while CD36 potentiates cancer metastasis. The effects of CD36 on proliferation/migration of breast cancer cells and tamoxifen-inhibited ER-positive cell growth are unknown. In this study, we correlated the mortality of breast cancer patients to tumor CD36 expression levels. We also found CD36 was higher in ER-rich (MCF-7>T-47D~ZR-75-30) than ER-negative (MDA-MB-231) cells. CD36 siRNA decreased viability and migration of MCF-7 and MDA-MB-231 cells with more potent effects on MCF-7 cells. Inversely, high expressing CD36 enhanced cell growth/migration. Mechanistically, CD36 increased expression of genes responsible for cell proliferation, migration and anti-apoptosis. CD36 also activated ERα and ER-targeted genes for cell cycles, and phosphorylated ERK1/2 (p-ERK1/2). Tamoxifen inhibited CD36 and p-ERK1/2 in ERα-positive but not ERα-negative cells. Reciprocally, inhibition of MCF-7 cell growth by tamoxifen was attenuated by high expressing CD36. CD36, ERα and p-ERK1/2 expression was higher in tamoxifen-resistant MCF-7 (MCF-7/TAMR) cells than normal MCF-7 cells. However, CD36 siRNA restored the capacity of tamoxifen inhibiting MCF-7/TAMR cell growth. CD36 antibody inhibited cell growth and expression of ERα, p-ERK1/2 and CCND1. Therefore, our study unveils a pro-tumorigenic role of CD36 in breast cancer by enhancing proliferation/migration of breast cancer cells while attenuating tamoxifen-inhibited ER-positive cell growth.
Highlights
Breast cancer, one of the most common diagnosed cancers, is the second leading cause of cancer death of women in the United States[1]
CD36 has been demonstrated to be involved in metastasis of various cancer types indicating its protumorigenic properties[17,19]
To determine if CD36 expression is involved in proliferation or migration of breast cancer cells in an ERdependent manner and influence the effect of tamoxifen on cell growth, we selected four types of breast cancer cell lines, MCF-7, ZR-75-30, MDA-MB-231 and T-47D cells
Summary
One of the most common diagnosed cancers, is the second leading cause of cancer death of women in the United States[1]. Breast cancers can be classified into several subtypes based on their distinct biological, molecular and clinical courses[2,3]. Tamoxifen functions as a selective estrogen receptor modulator based on the targeted cell types or molecules. It has been used for prevention and treatment of patients with breast cancers, with ERα-positive tumors, for several decades[5,6]. Tamoxifen can inhibit proliferation of ER-positive breast cancer cells by competitively binding to ERα. Tamoxifen activates apoptosis of breast cancer cells in an ERα-independent manner by regulating several signaling targets including protein kinase C, transforming
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