The Clinical Significance Of Scavenger Receptor Class B Type â…  Expression In Breast Cancer

BackgroundBreast cancer is a major public health problem among women worldwide. Interestingly, the morbidity of breast cancer is generally higher in western countries. In the United States, approximately 231,840 new cases of invasive breast cancer and 40,290 deaths are expected to occur among women in 2015. In China, breast cancer has become the most commonly diagnosed cancer in women. An upward trend in age-standardized incidence rate and age-standardized mortality rate was observed in breast cancer in recent years. Epidemiological studies have shown strong links between certain western lifestyles and breast cancer. Dietary fat intake, obesity and alcohol consumption may increase the risk of breast cancer. The serum lipoprotein profile of cancer patients indicated that the level of high-density lipoprotein (HDL) was the most affected during cancer progression.Scavenger receptor class B type I (SR-BI), an 82-kDa membrane glycoprotein, is a high-affinity HDL receptor that plays a key role in the reverse cholesterol transport process. Human SR-BI is primarily expressed in liver and steroidogenic tissues, such as adrenal gland, ovary and testis but not in normal breast tissue. SR-BI plays a crucial role in HDL metabolism, sepsis and hepatitis C virus entry. Several reports suggest complex associations between HDL and cancer, indicating a potential role for SR-BI in cancer. High SR-BI expression has been demonstrated in diverse cancer cell lines, including hepatoma, prostate, breast, colorectal, pancreatic, ovarian, and nasopharyngeal cancer. Danilo et al. reported that SR-BI participates in breast cancer development and progression by mediating the selective HDL-cholesteryl ester uptake and initiating PI3K/Akt signaling pathway. However, SR-BI expression in breast cancer and its clinical significance have not been addressed.In this context, we evaluated the expression of SR-BI using a high-throughput tissue microarray (TMA) containing 150 cases of breast carcinomas with the aim to explore its association with clinicopathological variables and patient outcome. Our results indicate that SR-BI high expression was associated with aggressive tumor behavior and had a negative impact on overall survival. Next, adult C57BL/6 mice were fed with normal diet (control),0.2% probucol or high fat diet to elucidate the effect of cholesterol lowering treatment and hyperlipidemia on mouse mammary SR-BI expression. The mammary SR-BI expression was not affected by probucol or high fat treatment exhibited by western blotting. Further researches that enroll larger samples and elucidate what causes the up-regulation of SR-BI are necessary and of great interest.Objective1. This study evaluated the expression of SR-BI using a high-throughput tissue microarray containing 150 cases of breast carcinomas.2. This study explored the association between SR-BI expression and clinicopathological variables and patient outcome to determine whether SR-BI expression was an independent prognostic factor and a potential therapeutic target for breast cancer.3. This study also aimed to elucidate the effect of cholesterol lowering treatment and hyperlipidemia on mouse mammary SR-BI expression.Methods1. In the present study, we evaluated the expression of SR-BI using a high-throughput tissue microarray containing 150 cases of breast carcinomas with the aim to explore its association with clinicopathological variables, and patient outcome.2. Adult C57BL/6 mice were fed with normal diet (control),0.2% probucol or high fat diet for 7 days. Plasma and mammary glands were harvested. The plasma cholesterol levels were measured with total cholesterol kit. SR-BI expression of the mammary glands was detected using western blotting.Results1. SR-BI protein was extensively expressed in breast cancer (> 90% of examined specimens). High expression was detected in 77 (54%), whereas low expression was seen in 66 (46%) out of 143 cases.2. High SR-BI expression was strongly associated with pTNM stage (P= 0.002), nodal stage (P= 0.012), ratio of positive nodes (P= 0.002), tumor size (P= 0.023) and the absence of ER (P= 0.014). However, no significant association of SR-BI expression with T stage, PR, HER2, triple-negative (ER-/PR-/HER2-) status, tumor grade and age was found.3. Patients with high SR-BI expression in breast cancer tissues had a significantly shorter OS than those with low SR-BI expression (log-rank test P= 0.004). The 10-year survival rate for breast cancer patients with low SR-BI expression was 80%, as compared to 60% in the group with high SR-BI expression. The multivariate analysis confirmed that high SR-BI expression was an independent unfavorable prognostic factor for OS, with the HR being 2.3 (P= 0.017). In addition to SR-BI, ER expression was also an independent prognostic factor for OS in breast cancer patients (P= 0.047).4. Mice plasma cholesterol level was lowered with probucol treatment (P= 0.022) and increased with high fat diet (P= 0.007), respectively.5. The mammary SR-BI expression was not affected by probucol or high fat treatment exhibited by western blotting.Conclusions1. High SR-BI expression was associated with conventional parameters indicative of more aggressive disease (advanced pTNM stage, higher N stage, larger tumor size and the absence of ER).2. High SR-BI expression independently predicts poor prognosis and may serve as a potential molecular target for breast carcinoma therapy.3. Cholesterol lowering drug or hyperlipidemia may not affect SR-BI expression in mice breast tissue.