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Absence of caveolin-1 alters heat shock protein expression in spontaneous mammary tumors driven by Her-2/neu expression

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Abstract

In a previous study, we measured caveolin-1 protein levels, both in the normal breast and in breast cancer. The study revealed no association between caveolin-1 expression in the epithelial compartment and clinical disease outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor associated strongly with reduced metastasis and improved survival. Using an animal model, we found that the onset of mammary tumors driven by Her-2/neu expression was accelerated in mice lacking caveolin-1. We have analysed the heat shock protein (Hsp) response in the tumors of mice lacking caveolin-1. In all cases, the mammary tumors were estrogen and progesterone receptor negative, and the levels of Her-2/neu (evaluated by immunohistochemistry) were not different between the caveolin-1 +/+ (n = 8) and the caveolin-1 −/− (n = 7) tumors. However, a significant reduction in the extent of apoptosis was observed in mammary tumors from animals lacking caveolin-1. While Bcl-2, Bax, and survivin levels in the tumors were not different, the amount of HSPA (Hsp70) was almost double in the caveolin-1 −/− tumors. In contrast, HSPB1 (Hsp27/Hsp25) levels were significantly lower in the caveolin-1 −/− tumors. The mammary tumors from caveolin-1 null mice expressed more HSPC4 (gp96 or grp94), but HSPC1 (Hsp90), HSPA5 (grp78), HSPD1 (Hsp60), and CHOP were not altered. No significant changes in these proteins were found in the stroma surrounding these tumors. These results demonstrate that the disruption of the Cav-1 gene can cause alterations of specific Hsps as well as tumor development.

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Abbreviations

ER:

Estrogen receptor

HSF-1:

Heat shock factor-1

Her-2/neu:

c-erbB-2

Hsp:

Heat shock protein

IHC:

Immunohistochemistry

PCNA:

Proliferating cell nuclear antigen

PR:

Progesterone receptor

References

  • Bausero MA, Bharti A, Page DT, Perez KD, Eng JWL, Jantschitsch C, Kindas-Muegge I, Ciocca D, Asea A (2006) Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell. Tumour Biol 27(1):17–26

    Article  PubMed  CAS  Google Scholar 

  • Black AT, Hayden PJ, Casillas RP, Heck DE, Gerecke DR, Sinko PJ, Laskin DL, Laskin JD (2011) Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide. Toxicol Appl Pharmacol 253(2):112–120

    Article  PubMed  CAS  Google Scholar 

  • Bocanegra V, Manucha W, Peña MR, Cacciamani V, Vallés PG (2010) Caveolin-1 and Hsp70 interaction in microdissected proximal tubules from spontaneously hypertensive rats as an effect of Losartan. J Hypertens 28(1):143–155

    Article  PubMed  CAS  Google Scholar 

  • Bosch M, Marí M, Herms A, Fernández A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, González-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, García-Ruiz C, Pérez-Navarro E, Fernández-Checa JC, Pol A (2011) Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr Biol 21(8):681–686

    Article  PubMed  CAS  Google Scholar 

  • Calderwood SK, Khaleque A, Sawyer DB, Ciocca DR (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31(3):164–172

    Article  PubMed  CAS  Google Scholar 

  • Castello-Cros R, Bonnuccelli G, Molchansky A, Capozza F, Witkiewicz AK, Birbe RC, Howell A, Pestell RG, Whitaker-Menezes D, Sotgia F, Lisanti MP (2011) Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis. Cell Cycle 10(12):2021–2034

    Article  PubMed  CAS  Google Scholar 

  • Cheng L, Smith DJ, Anderson RL, Nagley P (2011) Modulation of cellular Hsp72 levels in undifferentiated and neuron-like SH-SY5Y cells determines resistance to staurosporine-induced apoptosis. PloS One 6(9):e24473

    Article  PubMed  CAS  Google Scholar 

  • Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive and treatment implications. Cell Stress Chaperones 10(2):86–103

    Article  PubMed  CAS  Google Scholar 

  • Ciocca DR, Oesterreich GC, Chamness GC, McGuire WL, Fuqua SAW (1997) Heat shock protein 27, 000 (HSP 27): biological and clinical implications. J Natl Cancer Inst 85(19):1558–1570

    Google Scholar 

  • Ciocca DR, Gago FE, Fanelli MA, Calderwood SA (2006) Co-expression of steroid hormone receptors (estrogen receptor α and/or progesterone receptors) and Her2/neu: clinical implications. J Steroid Biochem Mol Biol 102(1–5):32–40

    Article  PubMed  CAS  Google Scholar 

  • Cipriani G, Serboiu Crenguta S, Gherghiceanu M, Faussone-Pellegrini MS, Vannucchi MG (2011) NK-receptors, substance P, Ano1 expression and ultrastructural features of the muscle coat in Cav-1(−/−) mouse ileum. J Cell Mol Med. doi:10.1111/j.1582-4934.2011.01333.x

  • Cuello-Carrión D, Ciocca DR (1999) Improved detection of apoptotic cells using the in situ TUNEL technique. J Histochem Cytochem 47(6):837–839

    Article  PubMed  Google Scholar 

  • Doshi BM, Hightower LE, Lee J (2009) The role of Hsp27 and actin in the regulation of movement in human cancer cells responding to heat shock. Cell Stress Chaperones 14(5):445–457

    Article  PubMed  CAS  Google Scholar 

  • Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293(5539):2449–2452

    Article  PubMed  CAS  Google Scholar 

  • Fanelli MA, Montt-Guevara M, Diblasi AM, Gago FE, Tello O, Cuello-Carrión FD, Callegary E, Bausero MA, Ciocca DR (2008) P-cadherin and β-catenin are useful prognostic markers in breast cancer patients; β-catenin interacts with heat shock protein Hsp27. Cell Stress Chaperones 13(2):207–220

    Article  PubMed  CAS  Google Scholar 

  • Gago FE, Tello OM, Diblasi AM, Ciocca DR (1998) Integration of estrogen and progesterone receptors with pathological and molecular prognostic factors in breast cancer patients. J Steroid Biochem Mol Biol 67(5–6):431–437

    Article  PubMed  CAS  Google Scholar 

  • Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70. Anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5(22):2592–2601

    Article  PubMed  CAS  Google Scholar 

  • Goetz JG, Lajoie P, Wiseman SM, Nabi IR (2008) Caveolin-1 in tumor progression: the good, the bad and the ugly. Cancer Metastasis Rev 27(4):715–735

    Article  PubMed  CAS  Google Scholar 

  • Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ (1992) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89(22):10578–10582

    Article  PubMed  CAS  Google Scholar 

  • Hu J, Shao S, Song Y, Zhao J, Dong Y, Gong L, Yang P (2010) Hepatocyte growth factor induces invasion and migration of ovarian cancer cells by decreasing the expression of e-cadherin, beta-catenin, and caveolin-1. Anat Rec (Hoboken) 293(7):1134–1139

    Article  CAS  Google Scholar 

  • Jin Y, Kim HP, Chi M, Ifedigbo E, Ryter SW, Choi AMK (2008) Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1. Am J Respir Cell Mol Biol 39(2):171–179

    Article  PubMed  CAS  Google Scholar 

  • Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Chetham ME, Chen B, Hightower LE (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14(1):105–111

    Article  PubMed  CAS  Google Scholar 

  • Kang SH, Kang KW, Kim KH, Kwon B, Kim SK, Lee HY, Kong SY, Lee ES, Jang SG, Yoo BC (2008) Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability. BMC Cancer 8:286. doi:10.1186/1471-2407-8-286

    Article  PubMed  Google Scholar 

  • Khaleque A, Bharti A, Gong J, Ciocca D, Stati A, Fanelli M, Calderwood SK (2008) Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1. Oncogene 27(13):1886–1893

    Article  PubMed  CAS  Google Scholar 

  • 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. doi:10.1007/s13277-011-0181-6

  • Lajoie P, Nabi IR (2010) Lipid rafts, caveolae, and their endocytosis. Int Rev Cell Mol Biol 282:135–163

    Article  PubMed  CAS  Google Scholar 

  • Li L, Ren C, Yang G, Goltsov AA, Tabata K, Thompson TC (2009) Caveolin-1 promotes autoregulatory, Akt-mediated induction of cancer-promoting growth factors in prostate cancer cells. Mol Cancer Res 7(11):1781–1791

    Article  PubMed  CAS  Google Scholar 

  • Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8(3):185–194

    Article  PubMed  CAS  Google Scholar 

  • Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2010) Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: a transcriptional informatics analysis with validation. Cell Cycle 9(11):2201–2219

    Article  PubMed  CAS  Google Scholar 

  • Santón A, García-Cosío M, Cristóbal E, Pascual A, Muriel A, García-Laraña J (2011) Expression of heat shock proteins in classical Hodgkin lymphoma: correlation with apoptotic pathways and prognostic significance. Histopathology 58(7):1072–1080

    Article  PubMed  Google Scholar 

  • Sloan EK, Ciocca DR, Pouliot N, Natoli A, Restall C, Henderson MA, Fanelli MA, Cuello-Carrión FD, Gago FE, Anderson RL (2009) Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am J Pathol 174(6):2035–2043

    Article  PubMed  CAS  Google Scholar 

  • Stankiewicz AR, Lachapelle G, Foo CP, Radicioni SM, Mosser DD (2005) Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 280(46):38729–38739

    Article  PubMed  CAS  Google Scholar 

  • Steel R, Doherty JP, Buzzard K, Clemons N, Hawkins CJ, Anderson RL (2004) Hsp72 inhibits apoptosis upstream of the mitochondria and not through interactions with Apaf-1. J Biol Chem 279(49):51490–51499

    Article  PubMed  CAS  Google Scholar 

  • Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE, Pestell RG, Sotgia F, Lisanti MP, Capozza F (2010) CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. Cancer Res 70(19):7489–7499

    Article  PubMed  CAS  Google Scholar 

  • Williams TM, Medina F, Badano I, Hazan RB, Hutchinson J, Muller WJ, Chopra NG, Scherer PE, Pestell RG, Lisanti MP (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(49):51630–51646

    Article  PubMed  CAS  Google Scholar 

  • Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, Kleer CG, Brody JR, Lisanti MP (2009a) An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol 174(6):2023–2034

    Article  PubMed  CAS  Google Scholar 

  • Witkiewicz AK, Dasgupta A, Nguyen KH, Liu C, Kovatich AJ, Schwartz GF, Pestell RG, Sotgia F, Rui H, Lisanti MP (2009b) Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer. Cancer Biol Ther 8(11):1071–1079

    Article  PubMed  CAS  Google Scholar 

  • Witkiewicz AK, Dasgupta A, Sammons S, Er O, Potoczek MB, Guiles F, Sotgia F, Brody JR, Mitchell EP, Lisanti MP (2010) Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers. Cancer Biol Ther 10(2):135–143

    Article  PubMed  Google Scholar 

  • Zhang M, Lin L, Lee SJ, Mo L, Cao J, Ifedigbo E, Jin Y (2009) Deletion of caveolin-1 protects hyperoxia-induced apoptosis via survivin-mediated pathways. Am J Physiol Lung Cell Mol Physiol 297(5):L945–L953

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Research Council of Argentina (CONICET) (PIP 2428 to DRC), the Agencia Nacional de Promoción Científica y Tecnológica of Argentina (PICT 1047, 2007, préstamo BID, DRC), the Argentina Foundation for Cancer Research (DRC) and by grants from the Susan G. Komen for the Cure (BCTR0403075 to RLA) and from the Cancer Council Victoria (RLA) and by a fellowship from the National Breast Cancer Foundation of Australia (RLA). This work is part of the Thesis (FDCC) for the PROBIOL, UNCuyo, Mendoza, Argentina.

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Authors and Affiliations

  1. Laboratory of Oncology, Institute of Experimental Medicine and Biology of Cuyo (MBECU), Technology and Scientific Center (CCT)-National Research Council of Argentina (CONICET), Ruiz Leal s/n, Parque General San Martín, 5500, Mendoza, Argentina

    Daniel R. Ciocca & F. Darío Cuello-Carrión

  2. Metastasis Research Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC, 3002, Australia

    Anthony L. Natoli, Christina Restall & Robin L. Anderson

  3. Department of Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia

    Robin L. Anderson

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  1. Daniel R. Ciocca
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  2. F. Darío Cuello-Carrión
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  3. Anthony L. Natoli
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  4. Christina Restall
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  5. Robin L. Anderson
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Corresponding author

Correspondence to Daniel R. Ciocca.

Additional information

D. R. Ciocca and F. D. Cuello-Carrión contributed equally to this work.

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Ciocca, D.R., Cuello-Carrión, F.D., Natoli, A.L. et al. Absence of caveolin-1 alters heat shock protein expression in spontaneous mammary tumors driven by Her-2/neu expression. Histochem Cell Biol 137, 187–194 (2012). https://doi.org/10.1007/s00418-011-0879-y

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