Abstract
The c-Src tyrosine kinase has been implicated to play an integral role in modulating growth factor receptor, integrin and steroid receptor function. One class of steroid receptors that c-Src modulates is the estrogen receptor α (ERα). Although there is strong biochemical evidence supporting a role for c-Src in ERα signaling, the consequence of this association is unclear at the biological level. To explore the significance of c-Src in ERα signaling, we studied the development of various reproductive organs that are dependent on ERα in c-Src-deficient mice. We show that the loss of the c-Src tyrosine kinase correlates with defects in ductal development as well as in uterine and ovarian development. Genetic and biochemical analyses of c-Src-deficient mammary epithelial cells also revealed defects in the ability of mammary epithelial cells to activate a number of signaling pathways in response to exogenous estrogen stimulation. Taken together, these studies demonstrate that c-Src plays a role in ERα signaling in vivo.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Andrechek ER, White D and Muller WJ . (2004). Oncogene, 21, 890–898.
Arnold SF, Melamed M, Vorojeikina DP, Notides AC and Sasson S . (1997). Mol. Endocrinol., 11, 48–53.
Arnold SF, Obourn JD, Jaffe H and Notides AC . (1995a). Mol. Endocrinol., 9, 24–33.
Arnold SF, Vorojeikina DP and Notides AC . (1995b). J. Biol. Chem., 270, 30205–30212.
Biswas R and Vonderhaar BK . (1987). Cancer Res., 47, 3509–3514.
Brisken C, Heineman A, Chavarria T, Elenbaas B, Tan J, Dey SK, McMahon JA, McMahon AP and Weinberg RA . (2000). Genes Dev., 14, 650–654.
Bunone G, Briand PA, Miksicek RJ and Picard D . (1996). EMBO J., 15, 2174–2183.
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S and Nakshatri H . (2001). J. Biol. Chem., 276, 9817–9824.
Carlomagno C, Perrone F, Gallo C, De Laurentiis M, Lauria R, Morabito A, Pettinato G, Panico L, D'Antonio A, Bianco AR and De Placido S . (1996). J. Clin. Oncol., 14, 2702–2708.
Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano D, Migliaccio A and Auricchio F . (1999). EMBO J., 18, 2500–2510.
Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV and Auricchio F . (2001). EMBO J., 20, 6050–6059.
Chan TO, Rodeck U, Chan AM, Kimmelman AC, Rittenhouse SE, Panayotou G and Tsichlis PN . (2002). Cancer Cell, 1, 181–191.
Cunha GR, Young P, Hom YK, Cooke PS, Taylor JA and Lubahn DB . (1997). J. Mammary Gland Biol. Neoplasia, 2, 393–402.
Dankort DL, Wang Z, Blackmore V, Moran MF and Muller WJ . (1997). Mol. Cell. Biol., 17, 5410–5425.
Datta K, Bellacosa A, Chan TO and Tsichlis PN . (1996). J. Biol. Chem., 271, 30835–30839.
Denton RR, Koszewski NJ and Notides AC . (1992). J. Biol. Chem., 267, 7263–7268.
De Placido S, Carlomagno C, De Laurentiis M and Bianco AR . (1998). Breast Cancer Res. Treat., 52, 55–64.
Di Domenico M, Castoria G, Bilancio A, Migliaccio A and Auricchio F . (1996). Cancer Res., 56, 4516–4521.
Fan M, Nakshatri H and Nephew KP . (2004). Mol. Endocrinol., 18, 2603–2615.
Frame S, Cohen P and Biondi RM . (2001). Mol. Cell, 7, 1321–1327.
Grunt TW, Saceda M, Martin MB, Lupu R, Dittrich E, Krupitza G, Harant H, Huber H and Dittrich C . (1995). Int. J. Cancer, 63, 560–567.
Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL and Altman DG . (1991). Br. J. Cancer, 63, 434–438.
Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, Adachi K, Tasaka K, Miyoshi E, Fujiwara N, Taniguchi N and Murata Y . (2001). J. Biol. Chem., 276, 3459–3467.
Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens RD and Miles DW . (1999). Br. J. Cancer, 79, 1220–1226.
Hutchinson J, Jin J, Cardiff RD, Woodgett JR and Muller WJ . (2001). Mol. Cell. Biol., 21, 2203–2212.
Jackson D, Bresnick J, Rosewell I, Crafton T, Poulsom R, Stamp G and Dickson C . (1997). J. Cell Sci., 110 (Part 11), 1261–1268.
Jackson-Fisher AJ, Bellinger G, Ramabhadran R, Morris JK, Lee KF and Stern DF . (2004). Proc. Natl. Acad. Sci. USA, 101, 17138–17143.
Joel PB, Traish AM and Lannigan DA . (1995). Mol. Endocrinol., 9, 1041–1052.
Joel PB, Traish AM and Lannigan DA . (1998). J. Biol. Chem., 273, 13317–13323.
Kaplan KB, Swedlow JR, Morgan DO and Varmus HE . (1995). Genes Dev., 9, 1505–1517.
Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D and Chambon P . (1995). Science, 270, 1491–1494.
Korach KS . (1994). Science, 266, 1524–1527.
Korach KS, Couse JF, Curtis SW, Washburn TF, Lindzey J, Kimbro KS, Eddy EM, Migliaccio S, Snedeker SM, Lubahn DB, Schomberg DW and Smith EP . (1996). Recent Prog. Horm. Res., 51, 159–186.
Lahooti H, White R, Danielian PS and Parker MG . (1994). Mol. Endocrinol., 8, 182–188.
Lahooti H, White R, Hoare SA, Rahman D, Pappin DJ and Parker MG . (1995). J. Steroid Biochem. Mol. Biol., 55, 305–313.
Le Goff P, Montano MM, Schodin DJ and Katzenellenbogen BS . (1994). J. Biol. Chem., 269, 4458–4466.
Lippman M, Bolan G and Huff K . (1976). Cancer Res., 36, 4595–4601.
Lonard DM, Nawaz Z, Smith CL and O'Malley BW . (2000). Mol. Cell, 5, 939–948.
Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS and Smithies O . (1993). Proc. Natl. Acad. Sci. USA, 90, 11162–11166.
Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C and Auricchio F . (2000). EMBO J., 19, 5406–5417.
Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E and Auricchio F . (1996). EMBO J., 15, 1292–1300.
Migliaccio A, Pagano M and Auricchio F . (1993). Oncogene, 8, 2183–2191.
Migliaccio A, Piccolo D, Castoria G, Di Domenico M, Bilancio A, Lombardi M, Gong W, Beato M and Auricchio F . (1998). EMBO J., 17, 2008–2018.
Migliaccio A, Rotondi A and Auricchio F . (1986). EMBO J., 5, 2867–2872.
Morelli C, Garofalo C, Bartucci M and Surmacz E . (2003). Oncogene, 22, 4007–4016.
Nawaz Z, Lonard DM, Dennis AP, Smith CL and O'Malley BW . (1999). Proc. Natl. Acad. Sci. USA, 96, 1858–1862.
Newman SP, Bates NP, Vernimmen D, Parker MG and Hurst HC . (2000). Oncogene, 19, 490–497.
Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, Gorman CM, Parker MG, Sliwkowski MX and Slamon DJ . (1995). Oncogene, 10, 2435–2446.
Prall OW, Rogan EM, Musgrove EA, Watts CK and Sutherland RL . (1998). Mol. Cell. Biol., 18, 4499–4508.
Prall OWJ, Sarcevic B, Musgrove EA, Watts CKW and Sutherland RL . (1997). J. Biol. Chem., 272, 10882–10894.
Reid G, Denger S, Kos M and Gannon F . (2002). Cell Mol. Life Sci., 59, 821–831.
Reid G, Hubner MR, Metivier R, Brand H, Denger S, Manu D, Beaudouin J, Ellenberg J and Gannon F . (2003). Mol. Cell, 11, 695–707.
Schomberg DW, Couse JF, Mukherjee A, Lubahn DB, Sar M, Mayo KE and Korach KS . (1999). Endocrinology, 140, 2733–2744.
Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ and Weinberg RA . (1995). Cell, 82, 621–630.
Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW and Liao JK . (2000). Nature, 407, 538–541.
Soriano P, Montgomery C, Geske R and Bradley A . (1991). Cell, 64, 693–702.
Stambolic V and Woodgett JR . (1994). Biochem. J., 303 (Part 3), 701–704.
Tepera SB, McCrea PD and Rosen JM . (2003). J. Cell Sci., 116, 1137–1149.
Webster MA, Cardiff RD and Muller WJ . (1995). Proc. Natl. Acad. Sci. USA, 92, 7849–7853.
White R, Sjoberg M, Kalkhoven E and Parker MG . (1997). EMBO J., 16, 1427–1435.
Wiesen JF, Young P, Werb Z and Cunha GR . (1999). Development, 126, 335–344.
Yudt MR, Vorojeikina D, Zhong L, Skafar DF, Sasson S, Gasiewicz TA and Notides AC . (1999). Biochemistry, 38, 14146–14156.
Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ and Bernards R . (1998). Genes Dev., 12, 3488–3498.
Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R and Michalides RJ . (1997). Cell, 88, 405–415.
Acknowledgements
We thank Dr P Schwartzberg for the c-Src251 plasmid used in this study. This work was supported by the United States Army Breast Cancer Research Initiative (DAMD17-01-1-0321). H Kim was supported by a scholarship from the Canadian Institutes of Health Research and WJ Muller is a recipient of a CRC Chair in Molecular Oncology.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, H., Laing, M. & Muller, W. c-Src-null mice exhibit defects in normal mammary gland development and ERα signaling. Oncogene 24, 5629–5636 (2005). https://doi.org/10.1038/sj.onc.1208718
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1208718
Keywords
This article is cited by
-
Distinct Requirements for Adaptor Proteins NCK1 and NCK2 in Mammary Gland Development
Journal of Mammary Gland Biology and Neoplasia (2023)
-
Insights from transgenic mouse models of PyMT-induced breast cancer: recapitulating human breast cancer progression in vivo
Oncogene (2021)
-
Actin filament-associated protein 1 is required for cSrc activity and secretory activation in the lactating mammary gland
Oncogene (2015)
-
Meaningful prevention of breast cancer metastasis: candidate therapeutics, preclinical validation, and clinical trial concerns
Journal of Molecular Medicine (2015)
-
Shorter disease-specific survival of ER-positive breast cancer patients with high cytoplasmic Src kinase expression after tamoxifen treatment
Journal of Cancer Research and Clinical Oncology (2012)