**10. ABCA1 in Cancer**

Cellular cholesterol homeostasis is highly regulated to maintain cell membrane integrity and to promote membrane-anchored signaling pathways, and this homeostasis is altered during cancer cell proliferation. Epidemiologic studies have associated high serum total cholesterol concentrations with decreased risk of cancer [298,299]. Furthermore, tumor cells have been found to show high levels of cholesterol, suggesting that cholesterol metabolism is increased in proliferating cancer tissues [300,301]. ABCA1-mediated cholesterol efflux is one of the major regulation pathways of cholesterol. Moreover, as cancer is a highly cooperative process of oncogenic mutations that causes multiple metabolic changes including changes in gene expression patterns, *ABCA1* was identified as one of the cooperation response genes, nonmutant genes synergistically downregulated by multiple cancer gene mutations in the processes of malignant cell transformation [302]. Thus, numerous studies have investigated the role of ABCA1 in cancer development.

There may be a dual role of ABCA1 in cancer, as several studies suggest that ABCA1 function has anticancer properties, although there is also epidemiological and experimental evidence suggesting it may be involved in progression of certain types of cancer. On one hand, diminished *ABCA1* expression in neoplastic breast and prostate tissue was associated with an increased rate of cancer cell proliferation [303,304]. Likewise, ABCA1 downregulation caused by *ABCA1* promoter hypermethylation, miR-183 degradation or loss of function mutations, led to elevated cholesterol levels in cancer cells, enhanced cell proliferation and inhibited apoptosis [305–309]. On the other hand, *ABCA1* has been classified as a member of a lipid metabolism gene expression signature (ColoLipidGene) related to poor prognosis in patients with colorectal cancer (CRC). This signature includes four overexpressed lipid metabolism-related genes [310]. ABCA1 has been proposed as a specific marker of triple-negative breast cancer (TNBC) since its expression was higher in TNBC tissues compared with noncancerous mammary tissues [311]. Additionally, highlevel expression of ABCA1 in primary tumors of serous ovarian cancer was associated with reduced survival of the patients and enhanced tumor cell growth and migration [312].

Several groups have provided insights into the molecular mechanisms of ABCA1 in cancer biology to help understand its pathophysiology and to identify potential therapeutic targets. Among the mechanisms proposed for ABCA1 anticancer activity are the following. (1) Deficient ABCA1-mediated cholesterol efflux increases intracellular and mitochondrial cholesterol levels, which decreases mitochondrial membrane fluidity and inhibits mitochondrial permeability transition. This avoids the release of cell death-promoting molecules such as cytochrome c and the apoptosis-inducing factor [308,313]. (2) ABCA1 activity has been linked to lipid raft disruption, by redistributing cholesterol and sphingomyelin from raft to nonraft domains. This results in reduced Akt signaling activation, which is sensitive to raft integrity. Akt upregulation has been associated with prostate cancer progression [314,315]. In other words, ABCA1 downregulation causes Akt upregulation, which in turn promotes cancer cell growth. (3) ABCA1 is known to suppress hematopoietic cell proliferation. Somatic *ABCA1* mutations found in chronic myelomonocytic leukemia

patients were found to impair cholesterol efflux and increase cell proliferation by enhancing the cholesterol-dependent IL3-receptor β pathway, which activates and protein-tyrosine kinase Janus kinase 2 (JAK2) and mitogen-activated protein kinase (MAPK) signaling [309] (Figure 3).

**Figure 3.** Proposed pathways of ABCA1 involvement in cancer. Downregulation of ABCA1 promotes cell growth and proliferation. a: ABCA1 downregulation avoids raft domain disruption and Akt pathway activation; b: ABCA1 downregulation causes cholesterol accumulation in the mitochondrial membrane inhibiting cytochrome c release and apoptosome formation; and c: ABCA1 downregulation activates the IL3-receptor, activating Janus kinase 2 (JAK2) and mitogen-activated protein kinase (MAPK) pathways. Upregulation of ABCA1 stabilizes caveolin-1 promoting epithelial-mesenchymal transition, and thus cell migration an invasion.

In contrast, other studies proposed mechanisms associated with ABCA1 activity in favor of cell cancer proliferation. For example, in colorectal cancer cell lines, ABCA1 overexpression led to an epithelial-to-mesenchymal transition and stabilized caveolin-1, known to promote cell migration, invasion, and has been proposed to be involved in tumor cell metastasis [316]. In addition, downregulated ABCA1 expression was found to prevent melanoma and bladder tumor growth in a syngeneic murine melanoma tumor model with a myeloid-specific *Abca1* deletion. Lack of Abca1 inhibited tumor bed accumulation of myeloid derived suppressor cells, known to promote tumor angiogenesis, metastasis and immune evasion, resulting in tumor growth inhibition [317].

Summarizing, although there is no conclusive evidence that ABCA1 is involved in the carcinogenesis process, unlike other members of the ABC transporter family (reviewed in [318]), it seems to play an important role in proliferation and survival of cancer cells. Moreover, while most studies suggest that ABCA1 activity is protective of cancer progression, there is also evidence of ABCA1 facilitating cell proliferation and tumor growth. Thus, the consequences of ABCA1 down or upregulation should be thoroughly investigated in different types and stages of cancer. Since intracellular cholesterol accumulation plays a key role in cancer progression, ABCA1 has been proposed as a potential therapeutic target; nevertheless, this subject needs further investigation.
