Abstract
Prolactin (PRL) is a polypeptidic hormone which acts both systemically and locally to cause lactation by interacting with the PRL receptor, a Janus kinase (JAK2)-coupled cytokine receptor family member. Several studies have reported that serum PRL level elevation is associated with an increased risk for breast cancer, and evidence has suggested that PRL is one actor in the pathogenesis and progression of this cancer. We previously reported the involvement of hIKCa1 in breast cell cycle progression and cell proliferation. However, mechanisms by which PRL cooperates with these channels to modulate breast epithelial cell proliferation remain unknown. Our results showed that, in the MCF-7 breast cancer cell line, PRL increased hIKCa1 current density. These channels were functional and regulated the resting membrane potential. The PRL effects were inhibited by TRAM-34 and clotrimazole, the most used hIKCa1 blockers. Moreover, PRL increased proliferation in a dose-dependent manner without overexpressing hIKCa1. To determine whether PRL-induced proliferation and hIKCa1 activity involved the JAK2 pathway, we used pharmacological JAK2 inhibitors (AG490 and JAK inhibitor I). Indeed, PRL-induced JAK2 phosphorylation was required for both cell proliferation and hIKCa1 activity. In the presence of either hIKCa1 blockers or siRNA-hIKCa1, PRL failed to increase cell proliferation and hIKCa1 activity. Taken together, our results demonstrate that PRL plays a role in breast cancer cell proliferation by increasing hIKCa1 activity through the JAK2 signaling pathway.
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References
Ali S, Pellegrini I, Kelly PA (1991) A prolactin-dependent immune cell line (Nb2) expresses a mutant form of prolactin receptor. J Biol Chem 266:20110–20117
Anantamongkol U, Takemura H, Suthiphongchai T, Krishnamra N, Horio Y (2007) Regulation of Ca2+ mobilization by prolactin in mammary gland cells: possible role of secretory pathway Ca2+-ATPase type 2. Biochem Biophys Res Commun 352:537–542
Biswas R, Vonderhaar BK (1987) Role of serum in the prolactin responsiveness of MCF-7 human breast cancer cells in long-term tissue culture. Cancer Res 47:3509–3514
Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA (1998) Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 19:225–268
Brockman JL, Schroeder MD, Schuler LA (2002) PRL activates the cyclin D1 promoter via the Jak2/Stat pathway. Mol Endocrinol 16:774–784
Clevenger CV, Plank TL (1997) Prolactin as an autocrine/paracrine factor in breast tissue. J Mammary Gland Biol Neoplasia 2:59–68
Clevenger CV, Chang WP, Ngo W, Pasha TL, Montone KT, Tomaszewski JE (1995) Expression of prolactin and prolactin receptor in human breast carcinoma. Evidence for an autocrine/paracrine loop. Am J Pathol 146:695–705
Clevenger CV, Furth PA, Hankinson SE, Schuler LA (2003) The role of prolactin in mammary carcinoma. Endocr Rev 24:1–27
Das R, Vonderhaar BK (1997) Prolactin as a mitogen in mammary cells. J Mammary Gland Biol Neoplasia 2:29–39
Ducret T, Boudina S, Sorin B, Vacher AM, Gourdou I, Liguoro D, Guerin J, Bresson-Bepoldin L, Vacher P (2002) Effects of prolactin on intracellular calcium concentration and cell proliferation in human glioma cells. Glia 38:200–214
Ducret T, Vacher AM, Vacher P (2004) Effects of prolactin on ionic membrane conductances in the human malignant astrocytoma cell line U87-MG. J Neurophysiol 91:1203–1216
Galsgaard ED, Rasmussen BB, Folkesson CG, Rasmussen LM, Berchtold MW, Christensen L, Panina S (2009) Re-evaluation of the prolactin receptor expression in human breast cancer. J Endocrinol 201:115–128
Gill S, Peston D, Vonderhaar BK, Shousha S (2001) Expression of prolactin receptors in normal, benign, and malignant breast tissue: an immunohistological study. J Clin Pathol 54:956–960
Ginsburg E, Vonderhaar BK (1995) Prolactin synthesis and secretion by human breast cancer cells. Cancer Res 55:2591–2595
Goffin V, Kinet S, Ferrag F, Binart N, Martial JA, Kelly PA (1996) Antagonistic properties of human prolactin analogs that show paradoxical agonistic activity in the Nb2 bioassay. J Biol Chem 271:16573–16579
Goffin V, Bernichtein S, Touraine P, Kelly PA (2005) Development and potential clinical uses of human prolactin receptor antagonists. Endocr Rev 26:400–422
Haren N, Khorsi F, Faouzi M, Ahidouch A, Sevestre H, Ouadid-Ahidouch H (2010) Intermediate conductance Ca2+ activated K+ channels are expressed and functional in breast adenocarcinomas: correlation with tumour grade and metastasis status. Histol Histopathol (in press)
Jager H, Dreker T, Buck A, Giehl K, Gress T, Grissmer S (2004) Blockage of intermediate-conductance Ca2+-activated K+ channels inhibit human pancreatic cancer cell growth in vitro. Mol Pharmacol 65:630–648
Liby K, Neltner B, Mohamet L, Menchen L, Ben-Jonathan N (2003) Prolactin overexpression by MDA-MB-435 human breast cancer cells accelerates tumor growth. Breast Cancer Res Treat 79:241–252
Llovera M, Pichard C, Bernichtein S, Jeay S, Touraine P, Kelly PA, Goffin V (2000) Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation. Oncogene 19:4695–4705
Mertani HC, Garcia-Caballero T, Lambert A, Gerard F, Palayer C, Boutin JM, Vonderhaar BK, Waters MJ, Lobie PE, Morel G (1998) Cellular expression of growth hormone and prolactin receptors in human breast disorders. Int J Cancer 79:202–211
Ouadid-Ahidouch H, Ahidouch A (2008) K+ channel expression in human breast cancer cells: involvement in cell cycle regulation and carcinogenesis. J Membr Biol 221:1–6
Ouadid-Ahidouch H, Roudbaraki M, Ahidouch A, Delcourt P, Prevarskaya N (2004a) Cell-cycle-dependent expression of the large Ca2+-activated K+ channels in breast cancer cells. Biochem Biophys Res Commun 316:244–251
Ouadid-Ahidouch H, Roudbaraki M, Delcourt P, Ahidouch A, Joury N, Prevarskaya N (2004b) Functional and molecular identification of intermediate-conductance Ca2+-activated K+ channels in breast cancer cells: association with cell cycle progression. Am J Physiol 287:C125–C134
Parihar AS, Coghlan MJ, Gopalakrishnan M, Shieh CC (2003) Effects of intermediate-conductance Ca2+-activated K+ channel modulators on human prostate cancer cell proliferation. Eur J Pharmacol 471:157–164
Peirce SK, Chen WY (2001) Quantification of prolactin receptor mRNA in multiple human tissues and cancer cell lines by real time RT-PCR. J Endocrinol 171:R1–R4
Prevarskaya N, Skryma R, Vacher P, Daniel N, Bignon C, Djiane J, Dufy B (1994) Early effects of PRL on ion conductances in CHO cells expressing PRL receptor. Am J Physiol 267:C554–C562
Prevarskaya NB, Skryma RN, Vacher P, Daniel N, Djiane J, Dufy B (1995) Role of tyrosine phosphorylation in potassium channel activation. Functional association with prolactin receptor and JAK2 tyrosine kinase. J Biol Chem 270:24292–24299
Ratovondrahona D, Fahmi M, Fournier B, Odessa MF, Skryma R, Prevarskaya N, Djiane J, Dufy B (1998) Prolactin induces an inward current through voltage-independent Ca2+ channels in Chinese hamster ovary cells stably expressing prolactin receptor. J Mol Endocrinol 21:85–95
Reynolds C, Montone KT, Powell CM, Tomaszewski JE, Clevenger CV (1997) Expression of prolactin and its receptor in human breast carcinoma. Endocrinology 138:5555–5560
Schroeder MD, Symowicz J, Schuler LA (2002) PRL modulates cell cycle regulators in mammary tumor epithelial cells. Mol Endocrinol 16:45–57
Sekine N, Ullrich S, Regazzi R, Pralong WF, Wollheim CB (1996) Postreceptor signaling of growth hormone and prolactin and their effects in the differentiated insulin-secreting cell line, INS-1. Endocrinology 137:1841–1850
Sorin B, Goupille O, Vacher AM, Paly J, Djiane J, Vacher P (1998) Distinct cytoplasmic regions of the prolactin receptor are required for prolactin-induced calcium entry. J Biol Chem 273:28461–28469
Swaminathan G, Varghese B, Thangavel C, Carbone CJ, Plotnikov A, Kumar KG, Jablonski EM, Clevenger CV, Goffin V, Deng L, Frank SJ, Fuchs SY (2008) Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2. J Endocrinol 196:R1–R7
Touraine P, Martini JF, Zafrani B, Durand JC, Labaille F, Malet C, Nicolas A, Trivin C, Postel-Vinay MC, Kuttenn F, Kelly PA (1998) Increased expression of prolactin receptor gene assessed by quantitative polymerase chain reaction in human breast tumors versus normal breast tissues. J Clin Endocrinol Metab 83:667–674
Tworoger SS, Hankinson SE (2008) Prolactin and breast cancer etiology: an epidemiologic perspective. J Mammary Gland Biol Neoplasia 13:41–53
Tworoger SS, Eliassen AH, Rosner B, Sluss P, Hankinson SE (2004) Plasma prolactin concentrations and risk of postmenopausal breast cancer. Cancer Res 64:6814–6819
Tworoger SS, Sluss P, Hankinson SE (2006) Association between plasma prolactin concentrations and risk of breast cancer among predominately premenopausal women. Cancer Res 66:2476–2482
Vacher P, Tran Van Chuoi M, Paly J, Djiane J, Dufy B (1994) Short term effect of prolactin on intracellular calcium in Chinese hamster ovary cells stably transfected with prolactin receptor complementary deoxyribonucleic acid. Endocrinology 134:1213–1218
Van Coppenolle F, Skryma R, Ouadid-Ahidouch H, Slomianny C, Roudbaraki M, Delcourt P, Dewailly E, Humez S, Crepin A, Gourdou I, Djiane J, Bonnal JL, Mauroy B, Prevarskaya N (2004) Prolactin stimulates cell proliferation through a long form of prolactin receptor and K+ channel activation. Biochem J 377:569–578
Vonderhaar BK (1999) Prolactin involvement in breast cancer. Endocr Relat Cancer 6:389–404
Wang ZH, Shen B, Yao HL, Jia YC, Ren J, Feng YJ, Wang YZ (2007) Blockage of intermediate-conductance Ca2+-activated K+ channels inhibits progression of human endometrial cancer. Oncogene 26:5107–5114
Acknowledgments
This work was supported by le conseil Régional de Picardie, le Ministère de l’Education Nationale, la Ligue contre le Cancer, l’Association pour la Recherche sur le Cancer and le Cancéropôle Nord Ouest.
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Malika Faouzi and Valérie Chopin have contributed equally to this work.
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Faouzi, M., Chopin, V., Ahidouch, A. et al. Intermediate Ca2+-Sensitive K+ Channels are Necessary for Prolactin-Induced Proliferation in Breast Cancer Cells. J Membrane Biol 234, 47–56 (2010). https://doi.org/10.1007/s00232-010-9238-5
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DOI: https://doi.org/10.1007/s00232-010-9238-5