Skip to main content
SpringerLink
Log in
Book cover

Protein Kinase C in Cancer Signaling and Therapy pp 347–360Cite as

PKC and Breast Cancer

  • Chapter
  • First Online:

  • 702 Accesses

Part of the book series: Current Cancer Research ((CUCR))

Abstract

PKC expression is intimately associated with breast cancer initiation, progression, and therapy responsiveness, and these effects are highly isozyme-specific. PKC isozymes play key roles in proliferation and apoptosis of breast cancer cells and exert important modulatory roles in cell cycle progression. A close relationship exists between specific PKC isozymes and estrogen signaling.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Alonso-Escolano, D., Medina, C., Cieslik, K., Radomski, A., Jurasz, P., Santos-Martínez, M. J., et al. (2006). Protein kinase Cδ mediates platelet induced breast cancer cell invasion. The Journal of Pharmacology and Experimental Therapeutics, 318, 373–380.

    Article  CAS  PubMed  Google Scholar 

  • Assender, J., Gee, J., Lewis, I., Ellis, I. O., Robertson, J. F., & Nicholson, R. I. (2007). Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer. Journal of Clinical Pathology, 60, 1216–1221.

    Article  CAS  PubMed  Google Scholar 

  • Basu, A., & Sivaprasad, U. (2007). Protein kinase Cε makes the life and death decision. Cell Signal, 19, 1633–1642.

    Article  CAS  PubMed  Google Scholar 

  • Brändlin, I., Hübner, S., Eiseler, T., Martinez-Moya, M., Horschinek, A., Hausser, A., et al. (2002). Protein kinase C (PKC)η-mediated PKCμ activation modulates ERK and JNK signal pathways. The Journal of Biological Chemistry, 8, 6490–6496.

    Article  Google Scholar 

  • Budworth, J., Gant, T., & Gescher, A. (1997). Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells. British Journal of Cancer, 75, 1330–1335.

    Article  CAS  PubMed  Google Scholar 

  • Charruyer, A., Jean, C., Columba, A., Jaffrézou, J. P., Quillet-Mary, A., Laurent, G., et al. (2007). PKCzeta protects against UV-C induced apoptosis by inhibiting acid sphingomyelinase-dependent ceramide production. Biochemical Journal, 405, 77–83.

    CAS  PubMed  Google Scholar 

  • de Vente, J. E., Kukoly, C. A., Bryant, W. O., Posekany, K. J., Chen, J., Fletcher, D. J., et al. (1995). Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms. The Journal of Clinical Investigation, 96, 1874–1886.

    Article  CAS  PubMed  Google Scholar 

  • Dean, N. M., McKay, R., Condon, T. P., & Bennett, C. F. (1994). Inhibition of protein kinase C-alpha expression in human A549 cells by antisense oligonucleotides inhibits induction of intercellular adhesion molecule 1 (ICAM-1) mRNA by phorbol esters. Journal of Biological Chemistry, 269, 16416–16424.

    CAS  PubMed  Google Scholar 

  • del Rincón, S., Guo, Q., Morelli, C., Shiu, H. Y., Surmacz, E., & Miller, W. H. (2004). Retinoic acid mediates degradation of IRS-1 by the ubiquitin-proteosome pathway, via a PKC-dependent mechanism. Oncogene, 23, 9269–9279.

    PubMed  Google Scholar 

  • Denning, M. F., Wang, Y., Nickoloff, B. J., & Wrone-Smith, T. (1998). Protein kinase C delta is activated by caspase-dependent proteolysis during ultraviolet radiation-induced apoptosis of human keratinocytes. Journal of Biological Chemistry, 273, 29995–30002.

    Article  CAS  PubMed  Google Scholar 

  • Foncea, R., Varela, S., Sapag-Hagar, M., & Lavandero, S. (1995). Changes in protein kinase C activity, subcellular distribution and protein phosphorylation during the lactogenic cycle in the rat mammary tissue. Research Communications in Molecular Pathology and Pharmacology, 87, 253–268.

    CAS  PubMed  Google Scholar 

  • Frankel, L. B., Lykkesfeldt, A. E., Hansen, J. B., & Stenvang, J. (2007). Protein kinase C alpha is a marker for antiestrogen resistance and is involved in the growth of tamoxifen resistant human breast cancer cells. Breast Cancer Research and Treatment, 104, 165–179.

    Article  CAS  PubMed  Google Scholar 

  • Gill, P., Gescher, A., & Gant, T. (2001). Regulation of MDR1 promoter activity in human breast carcinoma cells by protein kinase C isozymes α and θ. European Journal of Biochemistry, 268, 4151–4157.

    Article  CAS  PubMed  Google Scholar 

  • Greco, S., Elia, M. G., Muscella, A., Romano, S., Storelli, C., & Marsigliante, S. (2005). Bradykinin stimulates cell proliferation through an extracellular-regulated kinase 1 and 2-dependent mechanism in breast cancer cells in primary culture. The Journal of Endocrinology, 186, 291–301.

    Article  CAS  PubMed  Google Scholar 

  • Greco, S., Storelli, C., & Marsigliante, S. (2006). Protein kinase C (PKC)-δ/-ε mediate the PKC/Akt-dependent phosphorylation of extracellular signal-regulated kinases 1 and 2 in MCF-7 cells stimulated by bradykinin. The Journal of Endocrinology, 188, 79–89.

    Article  CAS  PubMed  Google Scholar 

  • Grossini, V., Falbo, K., Kazanietz, M., de Kier Joffé, E. D., & Urtreger, A. J. (2007). Protein kinase Cδ enhances proliferation and survival of murine mammary cells. Molecular Carcinogenesis, 46, 381–390.

    Article  Google Scholar 

  • Gubina, E., Rinaudo, M. S., Szallasi, Z., Blumberg, P. M., & Mufson, R. A. (1998). Overexpression of protein kinase C isoform epsilon but not delta in human interleukin-3-dependent cells suppresses apoptosis and induces bcl-2 expression. Blood, 91, 823–829.

    CAS  PubMed  Google Scholar 

  • Gupta, A. K., Galoforo, S. S., Berns, C. M., Martinez, A. A., Corry, P. M., Guan, K. L., et al. (1996). Elevated levels of ERK2 in human breast carcinoma MCF-7 cells transfected with protein kinase C alpha. Cell Proliferation, 29, 655–663.

    Article  CAS  PubMed  Google Scholar 

  • Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.

    Article  CAS  PubMed  Google Scholar 

  • Hovey, R. C., Trott, J. F., & Vonderhaar, B. K. (2002). Establishing a framework for the functional mammary gland: From endocrinology to morphology. Journal of Mammary Gland Biology and Neoplasia, 7, 17–38.

    Article  PubMed  Google Scholar 

  • Huang, L., Cheng, H., Isom, R., Chen, C. S., Levine, R. A., & Pauli, B. U. (2008). Protein kinase Cε mediates polymeric fibronectin assembly on the surface of blood-borne rat breast cancer cells to promote pulmonary metastasis. Journal of Biological Chemistry, 283, 7616–7627.

    Article  CAS  PubMed  Google Scholar 

  • Jackson, D., Zheng, Y., Lyo, D., Shen, Y., Nakayama, K., Nakayama, K. I., et al. (2005). Suppression of cell migration by protein kinase Cδ. Oncogene, 24, 3067–3072.

    Article  CAS  PubMed  Google Scholar 

  • Jasinski, P., Terai, K., Zwolak, P., & Dudek, A. Z. (2008). Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C. European Journal of Cancer, 44, 1315–1322.

    Article  CAS  PubMed  Google Scholar 

  • Karp, G., Maissel, A., & Livneh, E. (2007). Hormonal regulation of PKC: Estrogen up-regulates PKCη in estrogen-responsive breast cancer cells. Cancer Letters, 246, 173–181.

    Article  CAS  PubMed  Google Scholar 

  • Keshamouni, V., Mattingly, R., & Reddy, K. (2002). Mechanism of 17-β-Estradiol-induced Erk1/2 activation in breast cancer cells. Journal of Biological Chemistry, 277, 22558–22565.

    Article  CAS  PubMed  Google Scholar 

  • Kiley, S. C., Clark, K. J., Goodnough, M., Welch, D. R., & Jaken, S. (1999). Protein kinase C delta involvement in mammary tumor cell metastasis. Cancer Research, 59, 3230–3238.

    CAS  PubMed  Google Scholar 

  • Kim, E., Lee, H., Lee, D., Bae, S., Soh, J. W., Jeoung, D., et al. (2007). Inhibition of heat shock protein 27-mediated resistance to DNA damaging agents by a novel PKCδ-V5 heptapeptide. Cancer Research, 67, 6333–6341.

    Article  CAS  PubMed  Google Scholar 

  • Lahn, M., Köhler, G., Sundell, K., Su, C., Li, S., Paterson, B. M., et al. (2004). Protein kinase C alpha expression in breast and ovarian cancer. Oncology, 67, 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Lanigan, F., O’Conner, D., Martin, F., & Gallagher, W. M. (2007). Molecular links between mammary gland development and breast cancer. Cellular and Molecular Life Sciences, 64, 3161–3184.

    Article  CAS  Google Scholar 

  • Lavie, Y., Zhang, Z., Cao, H., Han, T. Y., Jones, R. C., Liu, Y. Y., et al. (1998). Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells. International Journal of Cancer, 77, 928–932.

    Article  CAS  Google Scholar 

  • Li, H., & Weinstein, I. B. (2006). Protein kinase C beta enhances growth and expression of cyclin D1 in human breast cancer cells. Cancer Research, 66, 11399–11408.

    Article  CAS  PubMed  Google Scholar 

  • Lin, C., Hou, W., Shen, S., Juan, S. H., Ko, C. H., Wang, L. M., et al. (2008). Quercetin inhibition of tumor invasion via suppressing PKCδ/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis, 29, 1807–1815.

    Article  CAS  PubMed  Google Scholar 

  • Lin, X., Yu, Y., Zhao, H., Zhang, Y., Manela, J., & Tonetti, D. A. (2006). Overexpression of PKC alpha is required to impart estradiol inhibition and tamoxifen-resistance in a T47D human breast cancer tumor model. Carcinogenesis, 27, 1538–1546.

    Article  CAS  PubMed  Google Scholar 

  • Lindemann, R., Braig, M., Hauser, C., Nordheim, A., & Dittmer, J. (2003). Ets2 and protein kinase Cε are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells. The Biochemical Journal, 372, 787–797.

    Article  CAS  PubMed  Google Scholar 

  • Lu, D., Huang, J., & Basu, A. (2006). Protein kinase Cε activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-α-induced cell death. Journal of Biological Chemistry, 281, 22799–22807.

    Article  CAS  PubMed  Google Scholar 

  • Lu, D., Sivaprasad, U., Huang, J., Shankar, E., Morrow, S., & Basu, A. (2007). Protein kinase C-ε protects MCF-7 cells from TNF-mediated cell death by inhibiting Bax translocation. Apoptosis, 12, 1893–1900.

    Article  CAS  PubMed  Google Scholar 

  • Masso-Welch, P. A., Verstovsek, G., Darcy, K., Tagliarino, C., & Ip, M. M. (1998). Protein kinase C eta upregulation and secretion during postnatal rat mammary gland differentiation. European Journal of Cell Biology, 77, 48–59.

    Article  CAS  PubMed  Google Scholar 

  • Masso-Welch, P. A., Verstovsek, G., & Ip, M. M. (1999). Alterations in the expression and localization of protein kinase C isoforms during mammary gland differentiation. European Journal of Cell Biology, 78, 497–510.

    Article  CAS  PubMed  Google Scholar 

  • Masso-Welch, P., Winston, J., & Edge, S. (2001). Altered expression and localization of PKC eta in human breast tumors. Breast Cancer Research and Treatment, 68, 211–223.

    Article  CAS  PubMed  Google Scholar 

  • McCracken, M., Miraglia, L., McKay, R., & Strobl, J. S. (2003). Protein kinase Cδ is a prosurvival factor in human breast tumor cell lines. Molecular Cancer Therapeutics, 2, 273–281.

    CAS  PubMed  Google Scholar 

  • Mingo-Sion, A., Ferguson, H., Koller, E., Reyland, M. E., & Van Den Berg, C. L. (2005). PKCδ and mTOR interact to regulate stress and IGF-I induced IRS-1 Ser312 phosphorylation in breast cancer cells. Breast Cancer Research and Treatment, 91, 259–269.

    Article  CAS  PubMed  Google Scholar 

  • Morse-Gaudio, M., Connolly, J. M., & Rose, D. P. (1998). Protein kinase C and its isoforms in human breast cancer cells: Relationship to the invasive phenotype. International Journal of Oncology, 12, 1349–1354.

    CAS  PubMed  Google Scholar 

  • Muscella, A., Greco, S., Elia, M., Storelli, C., & Marsigliante, S. (2003). PKC-ζ is required for angiotensin II-induced activation of ERK and synthesis of C-FOS in MCF-7 cells. Journal of Cellular Physiology, 197, 61–68.

    Article  CAS  PubMed  Google Scholar 

  • Nabha, S., Glaros, S., Hong, M., Lykkesfeldt, A. E., Schiff, R., Osborne, K., et al. (2005). Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells. Oncogene, 24, 3166–3176.

    Article  CAS  PubMed  Google Scholar 

  • Osborn, M. T., Berry, A., Ruberu, M. S., Ning, B., Bell, L. M., & Chambers, T. C. (1999). Phorbol ester induced MDR1 expression in K562 cells occurs independently of mitogen-activated protein kinase signaling pathways. Oncogene, 18, 5756–5764.

    Article  CAS  PubMed  Google Scholar 

  • Palmantier, R., George, M., Akiyama, S., Wolber, F. M., Olden, K., & Roberts, J. D. (2001). cis-Polyunsaturated fatty acids stimulate β1 integrin-mediated adhesion of human breast carcinoma cells to type IV collagen by activating protein kinases C-ε and -μ. Cancer Research, 61, 2445–2452.

    CAS  PubMed  Google Scholar 

  • Paz-Ares, L., Douillard, J. Y., Koralewski, P., Manegold, C., Smit, E. F., Reyes, J. M., et al. (2006). Phase III study of Gemcitabine and Cisplatin with or without Aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. Journal of Clinical Oncology, 24, 1428–1434.

    Article  CAS  PubMed  Google Scholar 

  • Ratnasinghe, D., Phang, J. M., & Yeh, G. C. (1998). Differential expression and activity of phosphatases and protein kinases in adriamycin sensitive and resistant human breast cancer MCF-7 cells. International Journal of Oncology, 13, 79–84.

    CAS  PubMed  Google Scholar 

  • Richert, M. M., Schwertfeger, K. L., Ryder, J. W., & Anderson, S. M. (2000). An atlas of mouse mammary gland development. Journal of Mammary Gland Biology and Neoplasia, 5, 227–241.

    Article  CAS  PubMed  Google Scholar 

  • Saenz, R., & Phillips, D. (1998). Breast Cancer. Primary Care, 25, 309–321.

    Article  CAS  PubMed  Google Scholar 

  • Sanz, L., Sanchez, P., Lallena, M., Diaz-Meco, M. T., & Mosat, J. (1999). The interaction of p62 with RIP links the atypical PKCs to NF-κB activation. The EMBO Journal, 18, 3044–3053.

    Article  CAS  PubMed  Google Scholar 

  • Shanmugam, M., Krett, N., Maizels, E., Cutler, R. E. Jr, Peters, C. A., Smith, L. M., et al. (1999). Regulation of protein kinase Cδ by estrogen in the MCF-7 human breast cancer cell line. Molecular and Cellular Endocrinology, 148, 109–118.

    Article  CAS  PubMed  Google Scholar 

  • Shanmugam, M., Krett, N. T., Maizels E. T., Murad, F. M., Rosen, S. T., & Hunzicker-Dunn, M. (2001). A role for protein kinase Cδ in the differential sensitivity of MCF-7 and MDA-MB 231 human breast cancer cells to phorbol esterinduced growth arrest and p21WAFI/CIP1 induction. Cancer Letters, 172, 43–53.

    Article  CAS  PubMed  Google Scholar 

  • Shtutman, M., Hershko, T., Maissel, A., Fima, E., & Livneh, E. (2003). PKCη associates with cyclin E/Cdk2 complex in serum-starved MCF-7 and NIH-3T3 cells. Experimental Cell Research, 286, 22–29.

    Article  CAS  PubMed  Google Scholar 

  • Sivaprasad, U., Shankar, E., & Basu, A. (2007). Downregulation of bid is associated with PKCε-mediated TRAIL resistance. Cell Death and Differentiation, 14, 851–860.

    Article  CAS  PubMed  Google Scholar 

  • Sledge, G. W., Jr., & Gökmen-Polar, Y. (2006). Protein kinase C-beta as a therapeutic target in breast cancer. Seminars in Oncology, 33(3 Suppl 9), S15–S18.

    Article  CAS  PubMed  Google Scholar 

  • Soh, J. W., Lee, Y. S., & Weinstein, I. B. (2003). Effects of regulatory domains of specific isoforms of protein kinase C on growth control and apoptosis in MCF-7 breast cancer cells. Journal of Experimental Therapeutics & Oncology, 3, 115–126.

    Article  CAS  Google Scholar 

  • Sun, R., Gao, P., Chen, L., Ma, D., Wang, J., Oppenheim, J. J., et al. (2005). Protein kinase Cζ is required for epidermal growth factor induced chemotaxis of human breast cancer cells. Cancer Research, 65, 1433–1441.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi, T., Ueno, H., & Shibuya, M. (1999). VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene, 18, 2221–2230.

    Article  CAS  PubMed  Google Scholar 

  • Tonetti, D. A., Chisamore, M. J., Grdina, W., Schurz, H., & Jordan, V. C. (2000). Stable transfection of protein kinase C alpha cDNA in hormone-dependent breast cancer cell lines. British Journal of Cancer, 83, 782–791.

    Article  CAS  PubMed  Google Scholar 

  • Ventura, A. C., Jackson, T. L., & Merajver, S. D. (2009). On the role of cell signaling models in cancer research. Cancer Research, 69, 400–402.

    Article  CAS  PubMed  Google Scholar 

  • Vucenik, I., Ramakrishna, G., Tantivejkul, K., Anderson, L. M., & Ramljak, D. (2005). Inositol hexaphosphate (IP6) blocks proliferation human breast cancer cells through a PKCδ-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation. Breast Cancer Research and Treatment, 91, 35–45.

    Article  CAS  PubMed  Google Scholar 

  • Wang, J., Wan, W., Sun, R., Liu, Y., Sun, X., Ma, D., et al. (2008). Reduction of Akt2 expression inhibits chemotaxis signal transduction in human breast cancer cells. Cell Signalling, 20, 1025–1034.

    Article  CAS  PubMed  Google Scholar 

  • Ways, D. K., Kukoly, C. A., deVente, J., Hooker, J. L., Bryant, W. O., Posekany, K. J., et al. (1995). MCF-7 breast cancer cells transfected with protein kinase C alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. Journal of Clinical Investigation, 95, 1906–1915.

    Article  CAS  PubMed  Google Scholar 

  • Williams, C. L., & Noti, J. D. (2001). Reduced expression of Wnt-1 and E-cadherin, and diminished beta-catenin stability in MCF-7 breast cancer cells that overexpress protein kinase C-alpha. International Journal of Oncology, 19, 1227–1233.

    CAS  PubMed  Google Scholar 

  • Xia, P., Aiello, L. P., Ishii, H., Jiang, Z. Y., Park, D. J., Robinson, G. S., et al. (1996). Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest, 98, 2018–2026.

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama, G., Fujii, T., Tayama, K., Yamana H, Kuwano, M., & Shirouzu, K. (2005). PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells. Biochemical and Biophysical Research Communications, 327, 720–726.

    Article  CAS  PubMed  Google Scholar 

  • Yu, G., Ahmad, S., Aquino, A., Fairchild, C. R., Trepel, J. B., Ohno, S., et al. (1991). Transfection with protein kinase C alpha confers increased multidrug resistance to MCF-7 cells expressing P-glycoprotein. Cancer Communications, 3, 181–189.

    CAS  PubMed  Google Scholar 

  • Zeidan, Y., Wu, B., Jenkins, R., Obeid, L. M., & Hannun, Y. A. (2008). A novel role for protein kinase Cδ-mediated phosphorylation of acid sphingomyelinase in UV light induced mitochondrial injury. The FASEB Journal, 22, 183–193.

    Article  CAS  Google Scholar 

  • Zhang, J., Liu, N., Zhang, J., Liu, S., Liu, Y., & Zheng, D. (2005). ΠΚΧδ protects human breast tumor MCF-7 cells against tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis. Journal of Cellular Biochemistry, 96, 522–532.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

    Sofia D. Merajver, Devin T. Rosenthal & Lauren Van Wassenhove

Authors
  1. Sofia D. Merajver
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Devin T. Rosenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lauren Van Wassenhove
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sofia D. Merajver .

Editor information

Editors and Affiliations

  1. School of Medicine, University of Pennsylvania, Curie Boulevard 421, Philadeliphia, 19147, USA

    Marcelo G. Kazanietz

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Merajver, S.D., Rosenthal, D.T., Van Wassenhove, L. (2010). PKC and Breast Cancer. In: Kazanietz, M. (eds) Protein Kinase C in Cancer Signaling and Therapy. Current Cancer Research. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-543-9_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-543-9_17

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-542-2

  • Online ISBN: 978-1-60761-543-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation