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http://dx.doi.org/10.7314/APJCP.2015.16.16.6803

Caveolin-1 in Breast Cancer: Single Molecule Regulation of Multiple Key Signaling Pathways  

Anwar, Sumadi Lukman (Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada)
Wahyono, Artanto (Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada)
Aryandono, Teguh (Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada)
Haryono, Samuel J (Mochtar Riady Comprehensive Cancer Center(MRCCC) Siloam Hospital Semanggi)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.16, no.16, 2015 , pp. 6803-6812 More about this Journal
Abstract
Caveolin-1 is a 22-kD trans-membrane protein enriched in particular plasma membrane invaginations known as caveolae. Cav-1 expression is often dysregulated in human breast cancers, being commonly upregulated in cancer cells and downregulated in stromal cells. As an intracellular scaffolding protein, Cav-1, is involved in several vital biological regulations including endocytosis, transcytosis, vesicular transport, and signaling pathways. Several pathways are modulated by Cav-1 including estrogen receptor, EGFR, Her2/neu, $TGF{\beta}$, and mTOR and represent as major drivers in mammary carcinogenesis. Expression and role of Cav-1 in breast carcinogenesis is highly variable depending on the stage of tumor development as well as context of the cell. However, recent data have shown that downregulation of Cav-1 expression in stromal breast tumors is associated with frequent relapse, resistance to therapy, and poor outcome. Modification of Cav-1 expression for translational cancer therapy is particularly challenging since numerous signaling pathways might be affected. This review focuses on present understanding of Cav-1 in breast carcinogenesis and its potential role as a new biomarker for predicting therapeutic response and prognosis as well as new target for therapeutic manipulation.
Keywords
Caveolin-1; breast cancer; signaling pathway; autophagy; prognosis; therapy;
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1 Witkiewicz AK, Kline J, Queenan M, et al (2011). Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle, 10, 1794-1809.   DOI
2 Witkiewicz AK, Dasgupta A, Nguyen K, et al (2009). Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer. Cancer Biol Ther, 8, 1071-9.   DOI
3 Wu P, Qi B, Zhu H, et al (2007). Suppression of staurosporinemediated apoptosis in Hs578T breast cells through inhibition of neutral-sphingomyelinase by caveolin-1. Cancer Lett, 256, 64-72.   DOI
4 Zagouri F, Sergentanis TN, Chrysikos D, Filipits M, Bartsch R, (2012). mTOR inhibitors in breast cancer: A systematic review. Gynecol Oncol, 127, 662-72.   DOI
5 Zhang EY, Cristofanilli M, Robertson F, et al (2013). Genome wide proteomics of ERBB2 and EGFR and other oncogenic pathways in inflammatory breast cancer. J Proteome Res, 12, 2805-17.   DOI
6 Zou W, McDaneld L, Smith LM, (2003). Caveolin-1 haploinsufficiency leads to partial transformation of human breast epithelial cells. AntiCancer Res, 23, 4581-6.
7 Agelaki S, Spiliotaki M, Markomanolaki H, et al (2009). Caveolin-1 regulates EGFR signaling in MCF-7 breast cancer cells and enhances gefitinib-induced tumor cell inhibition. Cancer Biol Ther, 8, 1470-7.   DOI
8 Bhowmick NA, Neilson EG, Moses HL (2004). Stromal fibroblasts in cancer initiation and progression. Nature, 432, 332-7.   DOI
9 Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, et al 2010. The reverse Warburg effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle, 9, 1960-71.   DOI
10 Bucci M, Gratton JP, Rudic RD, et al (2000). In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nat Med, 6, 1362-7.   DOI
11 Burke P, Schooler K, Wiley HS (2001). Regulation of epidermal growth factor receptor signaling by endocytosis and intracellular trafficking. Mol Biol Cell, 12, 1897-1910.   DOI
12 Cirri P, Chiarugi P (2011). Cancer associated fibroblasts : the dark side of the coin. Am J Cancer Res, 1, 482-97.
13 Cai C, Chen J (2004). Overexpression of caveolin-1 induces alteration of multidrug resistance in Hs578T breast adenocarcinoma cells. Int J Cancer, 111, 522-9.   DOI
14 Carroll JS, Meyer CA, Song J, et al (2006). Genome-wide analysis of estrogen receptor binding sites. Nat Genet, 38, 1289-97.   DOI
15 Castello-Cros R, Bonuccelli G, Molchansky A, et al (2011). Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis. Cell Cycle, 10, 2021-34.   DOI
16 Clemons M, Goss P (2001). Estrogen and the risk of breast cancer. NEJM, 344, 276-285.   DOI
17 Cohen AW, Razani B, Wang XB, et al (2003). Caveolin-1- deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am J Physiol Cell Physiol, 285, C222-5.   DOI
18 Dong X, Mao S, Wen H (2013). Upregulation of proinflammatory genes in skin lesions may be the cause of keloid formation (Review). Biomed Rep, 1, 833-6.
19 El-Gendi SM, Mostafa MF, El-Gendi AM, et al (2012). Stromal caveolin-1 expression in breast carcinoma. Correlation with early tumor recurrence and clinical outcome. Pathol Oncol Res, 18, 459-69.   DOI
20 Elsheikh SE, Green AR, Rakha EA, et al (2008). Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br J Cancer, 99, 327-34.   DOI
21 Van den Eynden GG, Van Laere SJ, Van der Auwera I, et al (2006).Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer. Breast Cancer Res Treat, 95, 219-28.   DOI
22 Fiucci G, Ravid D, Reich R, Liscovitch M, et al (2002). Caveolin-1 inhibits anchorage-independent growth anoikis and invasiveness in MFC-7 human breast cancer cells. Oncogene, 21, 2365-2375.   DOI
23 Fielding PE, Chau P, Liu D, Spencer TA, Fielding CJ, (2004). Mechanism of platelet-derived growth factor-dependent caveolin-1 phosphorylation: relationship to sterol binding and the role of serine-80. Biochemistry, 43, 2578-86.   DOI
24 Finn RS, Dering J, Ginther C (2007). Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/"triple-negative" breast cancer cell lines growing in vitro. Breast Cancer Res Treat, 105, 319-26.   DOI
25 Finn RS, Aleshin A, Dering J, et al (2013). Molecular subtype and response to dasatinib, an Src/Abl small molecule kinase inhibitor, in hepatocellular carcinoma cell lines in vitro. Hepatology, 57, 1838-46.   DOI
26 Fujita Y, Maruyama S, Kogo H, Matsuo S, Fujimoto T (2004). Caveolin-1 in mesangial cells suppresses MAP kinase activation and cell proliferation induced by bFGF and PDGF. Kidney Int, 66, 1794-04.   DOI
27 Giusiano S, Cochet C, Filhol O, et al (2011). Protein kinase $CK2{\alpha}$ subunit over-expression correlates with metastatic risk in breast carcinomas: Quantitative immunohistochemistry in tissue microarrays. Eur J Cancer, 47, 792-801.   DOI
28 Glait C, Ravid D, Lee SW, Liscovitch M, Werner H (2006). Caveolin-1 controls BRCA1 gene expression and cellular localization in human breast cancer cells. FEBS Lett, 580, 5268-74.   DOI
29 Goetz JG, Minguet S, Navarro-Lerida I, et al (2011). Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell, 146, 148-63.   DOI
30 Gupta R, Toufaily C, Annabi B (2014). Caveolin and cavin family members: dual roles in cancer. Biochimie, 107, 188-202.   DOI
31 Hayashi K, Matsuda S, Machida K, et al (2001). Invasion activating caveolin-1 mutation in human scirrhous breast cancers. Cancer Res, 61, 2361-64.
32 Hino M, Doihara H, Kobayashi K, Aoe M, Shimizu N (2003). Caveolin-1 as tumor suppressor gene in breast cancer. Surg Today, 33, 486-90.
33 Jezierska-Drutel A, Rosenzweig SA, Neumann CA, et al (2013). Role of oxidative stress and the microenvironment in breast cancer development and progression. Adv Cancer Res, 119, 107-25.   DOI
34 Joglekar M, Elbazanti WO, Weitzman MD, Lehma H, van Golen KL (2015). Caveolin-1 mediates inflamatory breast cancer cell invasion via the Akt1 pathway and RhoC GTPase. J Cell Biochem, 116, 923-33.   DOI
35 Kiss AL (2012). Caveolae and the regulation of endocytosis. Adv Exp Med Biol, 729, 14-28.   DOI
36 Koo JS, Park S, Kim SI, Lee S, Park BW (2011). The impact of caveolin protein expression in tumor stroma on prognosis of breast cancer. Tumour Biol, 32, 787-99.   DOI
37 Lajoie P, Nabi IR (2010). Lipid rafts, caveolae, and their endocytosis. Int Rev Cell Mol Biol, 282, 135-63.   DOI
38 Lavie Y, Fiucci G, Liscovitch M (2001). Upregulation of caveolin in multidrug resistant cancer cells: functional implications. Adv Drug Deliv Rev, 49, 317-23.   DOI
39 Lee H, Park DS, Razani B, et al (2002). Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia. Am J Pathol, 161, 1357-69.   DOI
40 Lee SW, Reimer CL, Oh P, Campbell DB, Schnitzer JE, (1998). Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene, 16, 1391-97.   DOI
41 Ma X, Liu L, Nie W, et al (2013). Prognostic role of caveolin in breast cancer: a meta-analysis. Breast, 22, 462-9.   DOI
42 Maldonado-Báez L, Williamson C, Donaldson JG (2013). Clathrin-independent endocytosis: A cargo-centric view. Exp Cell Res, 319, 2759-69.   DOI
43 Martinez-Outschoorn U, Sotgia F, Lisanti MP (2014). Tumor microenvironment and metabolic synergy in breast cancers: Critical importance of mitochondrial fuels and function. Semin Oncol, 41, 195-216.   DOI
44 Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker- Menezes D, et al (2010). Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NF${kappa}B$ activation in the tumor stromal microenvironment. Cell Cycle, 9, 3515-33.   DOI
45 Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, et al (2011). Cytokine production and inflammation drive autophagy in the tumor microenvironment: Role of stromal caveolin-1 as a key regulator. Cell Cycle, 10, 1784-93.   DOI
46 Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, et al (2010). Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle, 9, 2423-33.   DOI
47 Martinez-Outschoorn UE, Sotgia F, Lisanti MP, (2015). Caveolae and signalling in cancer. Nat Rev Cancer, 15, 225-37.   DOI
48 Mercier I, Lisanti M (2012). Caveolin-1 and breast cancer: a new clinical perspective. Adv Exp Med Biol, 729, 83-94.   DOI
49 Mercier I, Camacho J, Titchen K, et al (2012). Caveolin-1 and accelerated host aging in the breast tumor microenvironment: Chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug. Am J Pathol, 181, 278-93.   DOI
50 Mercier I, Casimiro MC, Wang C, et al (2008). Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy. Cancer Biol Ther, 7, 1212-25.   DOI
51 Mercier I, Lisanti MP (2012). Caveolin-1 and breast cancer: a new clinical perspective. caveolins and caveolae: roles in signaling and disease mechanisms. Adv Exp Med Biol, 729, 83-94.   DOI
52 Mineo C, Gill GN, Anderson RGW, (1999). Regulated migration of epidermal growth factor receptor from caveolae. J Biol Chem, 274, 30636-43.   DOI
53 Orom UA, Lim MK, Savage JE, et al (2012). MicroRNA-203 regulates caveolin-1 in breast tissue during caloric restriction. Cell Cycle, 11, 1291-5.   DOI
54 Otranto M, Sarrazy V, Bonte F, et al (2012). The role of the myofibroblast in tumor stroma remodeling. Cell Adh Mig, 6, 203-19.   DOI
55 Park DS, Lee H, Frank PG, et al (2002). Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade. Mol Biol Cell, 13, 3416-30.   DOI
56 Park JH, Han HJ (2009). Caveolin-1 plays important role in EGFinduced migration and proliferation of mouse embryonic stem cells: involvement of PI3K/Akt and ERK. Am J Physiol Cell Physiol, 297, 935-44.   DOI
57 Patani N, Lambros MB, Natrajan R, et al (2012). Non-existence of caveolin-1 gene mutations in human breast cancer. Breast Cancer Res Treat, 131, 307-10.   DOI
58 Park JH, Lee MY, Han HJ, et al (2009). A potential role for caveolin-1 in estradiol-17beta-induced proliferation of mouse embryonic stem cells: involvement of Src, PI3K/Akt, and MAPKs pathways. Int J Biochem Cell Biol, 41, 659-65.   DOI
59 Park SS, Kim JE, Kim YA, Kim YC, Kim SW (2005). Caveolin-1 is down-regulated and inversely correlated with HER2 and EGFR expression status in invasive ductal carcinoma of the breast. Histopathology, 47, 625-30.   DOI
60 Park WY, Park JS, Cho KA, et al (2000). Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells. J Biol Chem, 275, 20847-52.   DOI
61 Patani N, Martin LA, Reis-Filho JS, Dowsett M, (2012). The role of caveolin-1 in human breast cancer. Breast Cancer Res Treat, 131, 1-15.   DOI
62 Pavlides S, Tsirigos A, Migneco G, et al (2010). The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle, 9, 3485-505.   DOI
63 White BP, Molloy MP, Zhao H, et al (2013). Extranuclear ERalpha is associated with regression of T47D PKCalphaoverexpressing, tamoxifen-resistant breast cancer. Mol Cancer, 12, 34.   DOI
64 Perrone G, Altomare V, Zagami M, et al (2009). Caveolin-1 expression in human breast lobular cancer progression. Mod Pathol, 22, 71-8.   DOI
65 Qian N, Ueno T, Kawaguchi-Sakita N, et al (2011). Prognostic significance of tumor/stromal caveolin-1 expression in breast cancer patients. Cancer Sci, 102, 1590-6.   DOI
66 Sagara Y, Mimori K, Yoshinaga K, et al (2004). Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer. Br J Cancer, 91, 959-65.
67 Rao X, Evans J, Chae H, et al (2012). CpG island shore methylation regulates caveolin-1 expression in breast cancer. Oncogene, 32, 4519-28
68 Ren M, Liu F, Zhu Y, et al (2014). Absence of caveolin-1 expression in carcinoma associated fibroblast of invasive micropapollary carcinoma of the breast predicts poor patient outcome. Virchows Arch, 465, 291-8.   DOI
69 Pinilla SM, Honrado E, Hardisson D, Benítez J, Palacios J, (2006). Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat, 99, 85-90.   DOI
70 Savage K, Lambros MB, Robertson D, et al (2007). Caveolin 1 is overexpressed and amplified in a subset of basallike and metaplastic breast carcinomas: A morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis. Clin Cancer Res, 13, 90-101.   DOI
71 Schlegel A, Wang C, Katzenellenbogen BS, Pestell RG, Lisanti MP, (1999). Caveolin-1 potentiates estrogen receptor ${\alpha}$ (ER ${\alpha}$) signaling. Caveolin-1 drives ligand-independent nuclear translocation and activation of ER ${\aopha}$. J Biol Chem, 274, 33551-6.   DOI
72 Schlegel A, Wang C, Pestell RG, Lisanti MP, (2001). Ligandindependent activation of oestrogen receptor alpha by caveolin-1. Bioch J, 359, 203-10.   DOI
73 Sekhar SC, Kasai T, Satoh A, et al (2013). Identification of caveolin-1 as a potential causative factor in the generation of trastuzumab resistance in breast cancer cells. J Cancer, 4, 391-401.   DOI
74 Simpkins SA, Hanby AM, Holliday DL, Speirs V, (2012). Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J Pathol, 227, 490-8.   DOI
75 Senetta R, Stella G, Pozzi E, et al (2013). Caveolin-1 as a promoter of tumour spreading: When, how, where and why. J Cell Mol Med, 17, 325-36.   DOI
76 Shajahan AN, Dobbin ZC, Hickman FE, Dakshanamurthy S, Clarke R, (2012). Tyrosine-phosphorylated caveolin-1 (Tyr- 14) increases sensitivity to paclitaxel by inhibiting BCL2 and BCLxL proteins via c-Jun N-terminal Kinase (JNK). J Biol Chem, 287, 17682-92.   DOI
77 Siegel R, Ma J, Zou Z, Jemal A, (2014). Cancer statistics, 2014. CA Cancer J Clin, 64, 9-29.   DOI
78 Sloan EK, Ciocca DR, Pouliot N, et al (2009). Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am J Pathol, 174, 2035-43.   DOI
79 Sloan EK, Stanley KL, Anderson RL, (2004). Caveolin-1 inhibits breast cancer growth and metastasis. Oncogene, 23, 7893-7.   DOI
80 Sotgia F (2012). Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment: Markers, Models, and Mechanisms. Annual Review of Pathology: Mechanisms of Disease, 7, 423-467.   DOI
81 Sotgia F, Martinez-Outschoorn UE, Howell A, et al (2006). Caveolin-1, mammary stem cells, and estrogen-dependent breast cancers. Cancer Res, 66, 10647-51.   DOI
82 Sotgia F, Martinez-Outschoorn UE, Pavlides S, et al (2011). Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Br Cancer Res, 13, 213.   DOI
83 Thomas NB, Hutcheson IR, Campbell L, et al (2010). Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance. Breast Cancer Res Treat, 119, 575-91.   DOI
84 Syeed N, Husain SA, Abdullah S, et al (2010). Caveolin-1 promotes mammary tumorigenesis: Mutational profile of the Kashmiri population. Asian Pac J Cancer Prev, 11, 689-96.
85 Syeed N, Husain SA, Abdullah S, et al (2010). Mutational profile of the CAV-1 gene in breast cancer cases in the ethnic Kashmiri population. Asian Pac J Cancer Prev, 11, 1099-105.
86 Tagawa A, Mezzacasa A, Hayer A, et al (2005). Assembly and trafficking of caveolar domains in the cell: Caveolae as stable, cargo-triggered, vesicular transporters. J Cell Biol, 170, 769-79.   DOI
87 Tian F, Wu H, Li Z, et al (2009). Activated PKCalpha/ERK1/2 signaling inhibits tamoxifen-induced apoptosis in C6 cells. Cancer Invest, 27, 802-8.   DOI
88 Trimmer C, Sotgia F, Whitaker-Menezes D, et al (2011). Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: A new genetically tractable model for human cancer associated fibroblasts. Cancer Biol Ther, 11, 383-94.   DOI
89 Tryfonopoulos D, Walsh S, Collins DM, et al (2011). Src: a potential target for the treatment of triple-negative breast cancer. Ann Oncol, 22, 2234-40.   DOI
90 Wang XX, Wu Z, Huang HF, et al (2013). Caveolin-1, through its ability to negatively regulate TLR4, is a crucial determinant of MAPK activation in LPS-challenged mammary epithelial cells. Asian Pac J Cancer Prev, 14, 2295-9.   DOI
91 Williams TM, Medina F, Badano I, et al (2004). Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo: Role of Cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion. J Biol Chem, 279, 51630-46.   DOI
92 Wang Y, Yu J, Zhan Q (2008). BRCA1 regulates caveolin-1 expression and inhibits cell invasiveness. Biochem Biophys Res Commun, 370, 201-6.   DOI
93 Wang Z, Wang N, Li W, et al (2014). Caveolin-1 mediates chemoresistance in breast cancer stem cells via ${\beta}$-catenin/ ABCG2 signaling pathway. Carcinogenesis, 35, 2346-56.   DOI
94 Weigelt B, Geyer FC, Natrajan R, et al (2010). The molecular underpinning of lobular histological growth pattern: A genome-wide transcriptomic analysis of invasive lobular carcinomas and grade- and molecular subtype-matched invasive ductal carcinomas of no special type. J Pathol, 220, 45-57.   DOI
95 Williams TM, Lee H, Cheung MW, et al (2004). Combined loss of INK4a and caveolin-1 synergistically enhances cell proliferation and oncogene-induced tumorigenesis. Role of INK4a/CAV-1 in mammary epithelial cell hyperplasia. J Bioll Chem, 279, 24745-56.   DOI
96 Williams TM, Lisanti MP, (2005). Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am J Physiol Cell Physiol, 288, 494-506.
97 Williams TM, Lisanti MP, (2004). The caveolin proteins. Genome Biol, 5, 214.   DOI
98 Witkiewicz AK, Dasgupta A, Sotgia F, et al (2009). An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol, 174, 2023-34.   DOI