Prostate cancer is the most commonly diagnosed malignancy in men and it has the potential to progress to a metastatic and highly aggressive form of cancer, which is still difficult to cure. Therefore, it is of profound importance to identify markers that allow the prediction of prostate cancer progression to its aggressive metastatic form. Recent studies suggest that cholesterol plays a major role in prostate cancer [
15,
22‐
24]. In human cells, cholesterol uptake is mainly based on two pathways: receptor-mediated endocytosis by the LDL receptor and selective lipid uptake by SR-BI [
6‐
8]. Here, we show an association of prostate cancer malignancy with the expression of the HDL receptor SR-BI. Our analysis of 306 clinical prostate samples for mRNA and 106 prostate tissue biopsy cores for protein expression identified significantly higher SR-BI expression in high Gleason grade versus low Gleason grade prostate cancer samples. Furthermore, our analysis of gene expression profiles identified significantly higher SR-BI mRNA expression in metastatic compared to non-metastatic prostate cancer. Strikingly, we further discovered an association of SR-BI expression with disease-free survival time in a cohort of 85 clinical prostate samples. Previous studies already suggested a connection of SR-BI expression with prostate cancer: the knockdown of SR-BI has been shown to reduce PSA levels and the viability of prostate cancer cells
in vitro [
15]. Moreover, SR-BI was found to be significantly up-regulated with progression to lethal castration-resistant prostate cancer (CRPC) in an LNCaP xenograft mouse model [
25], while androgen-tolerant LNCaP cells
in vitro did not show SR-BI up-regulation [
26]. SR-BI has further been linked to nasopharyngeal cancer [
27], colorectal cancer [
28], ovarian cancer [
28] and most notably breast cancer [
29,
30], a tumor strongly dependent on the synthesis of sexual hormones. Furthermore, it was demonstrated that mutations of SR-BI affected the proliferation and apoptosis of the breast cancer cell line MCF-7 [
30]. Knockdown of SR-BI was shown to inhibit proliferation and migration in breast cancer, and SR-BI knockdown also caused a decrease of tumor growth in MDA-MB231 and MCF-7 breast cancer cells
in vivo when injected into nude mice [
29].
The mTOR pathway plays a key role in the regulation of cellular growth and metabolism [
31,
32]. Together with raptor and LST8, mTOR forms a complex called mTORC1 (mTOR complex 1), which acts by activating the ribosomal protein S6 through the protein kinase S6K1 [
31,
32]. It is further known that mTORC1 influences cholesterol synthesis and uptake via the SREBP pathway [
33‐
35]. Recently, it was shown that the inhibition of mTOR via rapamycin down-regulates SR-BI expression in human umbilical vein endothelial cells, indicating a direct connection between mTOR activation and SR-BI expression [
36]. Further, it is known that mTOR plays a crucial role in the progression of prostate cancer to CRPC by influencing the androgen signaling pathway [
37,
38]. According to our results, pS6 expression significantly correlates with SR-BI expression, which suggests the regulation of SR-BI by mTORC1 in prostate cancer.
To our knowledge, SR-BI has not been thoroughly studied in clinical samples of prostate cancer, and our findings on the mRNA and protein expression of SR-BI can contribute substantially to our understanding of prostate cancer progression. This study demonstrates the high expression of SR-BI in de-differentiated and metastasized prostate cancer, which almost always acquires resistance to androgen depletion. Therefore, we suggest that increased levels of SR-BI are involved in the transport of cholesterol into the tumor cell. This uptake of cholesterol could be exploited by the cancer cell to up-regulate its androgen synthesis. We observed the up-regulation of 3β- and 17β-hydroxysteroid dehydrogenases, which may play an important yet unclear role in intra-tumoral androgen synthesis [
39,
40]. This process may contribute to the generation of castration-resistant prostate cancer. Therefore, pharmacologic inhibition of the HDL receptor might represent a way to inhibit prostate cancer progression. We suggest that SR-BI may be a valuable target for prostate cancer therapy; therefore, we strongly recommend that further studies investigate the role of SR-BI during prostate cancer progression.