Carcinoma-associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: A role for the FGF-2/FGFR-2 axis
Sebastián Giulianelli
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorJuan P. Cerliani
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorCaroline A. Lamb
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorVictoria T. Fabris
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría C. Bottino
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría A. Gorostiaga
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorVirginia Novaro
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorAdrián Góngora
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorAlberto Baldi
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorAlfredo Molinolo
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorCorresponding Author
Claudia Lanari
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Fax: +054-011-4786-2564
IBYME, Obligado 2490, 1428 Buenos Aires, ArgentinaSearch for more papers by this authorSebastián Giulianelli
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorJuan P. Cerliani
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorCaroline A. Lamb
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorVictoria T. Fabris
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría C. Bottino
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorMaría A. Gorostiaga
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorVirginia Novaro
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorAdrián Góngora
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorAlberto Baldi
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorAlfredo Molinolo
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Search for more papers by this authorCorresponding Author
Claudia Lanari
Laboratory of Hormonal Carcinogenesis, Institute of Experimental Biology and Medicine (IBYME)-National Research Council of Argentina (CONICET), Buenos Aires, Argentina
Fax: +054-011-4786-2564
IBYME, Obligado 2490, 1428 Buenos Aires, ArgentinaSearch for more papers by this authorAbstract
The mechanisms by which mammary carcinomas acquire hormone independence are still unknown. To study the role of cancer-associated fibroblasts (CAF) in the acquisition of hormone-independence we used a hormone-dependent (HD) mouse mammary tumor and its hormone-independent (HI) variant, which grows in vivo without hormone supply. HI tumors express higher levels of FGFR-2 than HD tumors. In spite of their in vivo differences, both tumors have the same hormone requirement in primary cultures. We demonstrated that CAF from HI tumors (CAF-HI) growing in vitro, express higher levels of FGF-2 than HD counterparts (CAF-HD). FGF-2 activated the progesterone receptors (PR) in the tumor cells, thus increasing cell proliferation in both HI and HD tumors. CAF-HI induced a higher proliferative rate on the tumor cells and in PR activation than CAF-HD. The blockage of FGF-2 in the co-cultures or the genetic or pharmacological inhibition of FGFR-2 inhibited PR activation and tumor cell proliferation. Moreover, in vivo, the FGFR inhibitor decreased C4-HI tumor growth, whereas FGF-2 was able to stimulate C4-HD tumor growth as MPA. T47D human breast cancer cells were also stimulated by progestins, FGF-2 or CAF-HI, and this stimulation was abrogated by antiprogestins, suggesting that the murine C4-HI cells respond as the human T47D cells. In summary, this is the first study reporting differences between CAF from HD and HI tumors suggesting that CAF-HI actively participate in driving HI tumor growth. © 2008 Wiley-Liss, Inc.
References
- 1 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285: 1182–6.
- 2 Shekhar MP,Pauley R,Heppner G. Host microenvironment in breast cancer development: extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res 2003; 5: 130–5.
- 3 Cunha GR,Hayward SW,Wang YZ,Ricke WA. Role of the stromal microenvironment in carcinogenesis of the prostate. Int J Cancer 2003; 107: 1–10.
- 4 Sternlicht MD,Lochter A,Sympson CJ,Huey B,Rougier JP,Gray JW,Pinkel D,Bissell MJ,Werb Z. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999; 98: 137–46.
- 5 Tlsty TD,Hein PW. Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 2001; 11: 54–9.
- 6 Maffini MV,Soto AM,Calabro JM,Ucci AA,Sonnenschein C. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004; 117: 1495–502.
- 7 Barcellos-Hoff MH,Ravani SA. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 2000; 60: 1254–60.
- 8 Micke P,Ostman A. Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy. Expert Opin Ther Targets 2005; 9: 1217–33.
- 9 Sappino AP,Skalli O,Jackson B,Schurch W,Gabbiani G. Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int J Cancer 1988; 41: 707–12.
- 10 Orimo A,Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 2006; 5: 1597–601.
- 11 Orimo A,Gupta PB,Sgroi DC,Arenzana-Seisdedos F,Delaunay T,Naeem R,Carey VJ,Richardson AL,Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121: 335–48.
- 12 Zhang HZ,Bennett JM,Smith KT,Sunil N,Haslam SZ. Estrogen mediates mammary epithelial cell proliferation in serum-free culture indirectly via mammary stroma-derived hepatocyte growth factor. Endocrinology 2002; 143: 3427–34.
- 13 Thomson AA. Role of androgens and fibroblast growth factors in prostatic development. Reproduction 2001; 121: 187–95.
- 14 Lanari C,Kordon E,Molinolo A,Pasqualini CD,Charreau EH. Mammary adenocarcinomas induced by medroxyprogesterone acetate: hormone dependence and EGF receptors of BALB/c in vivo sublines. Int J Cancer 1989; 43: 845–50.
- 15 Montecchia MF,Lamb C,Molinolo AA,Luthy IA,Pazos P,Charreau E,Vanzulli S,Lanari C. Progesterone receptor involvement in independent tumor growth in MPA-induced murine mammary adenocarcinomas. J Steroid Biochem Mol Biol 1999; 68: 11–21.
- 16 Lamb C,Simian M,Molinolo A,Pazos P,Lanari C. Regulation of cell growth of a progestin-dependent murine mammary carcinoma in vitro: progesterone receptor involvement in serum or growth factor-induced cell proliferation. J Steroid Biochem Mol Biol 1999; 70: 133–42.
- 17 Lamb CA,Helguero LA,Giulianelli S,Soldati R,Vanzulli SI,Molinolo A,Lanari C Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice. Breast Cancer Res 2005; 7: R1111–21.
- 18 Institute of Laboratory Animal Resources, Commission on Life Sciences National Research Council. Guide for the care and use of laboratory animals. Washington, D.C.: National Academy Press, 1996.
- 19 Lanari C,Luthy I,Lamb CA,Fabris V,Pagano E,Helguero LA,Sanjuan N,Merani S,Molinolo AA. Five novel hormone-responsive cell lines derived from murine mammary ductal carcinomas: in vivo and in vitro effects of estrogens and progestins. Cancer Res 2001; 61: 293–302.
- 20 Dran G,Luthy IA,Molinolo AA,Charreau EH,Pasqualini CD,Lanari C. Effect of medroxyprogesterone acetate (MPA) and serum factors on cell proliferation in primary cultures of an MPA-induced mammary adenocarcinoma. Breast Cancer Res Treat 1995; 35: 173–86.
- 21 Fabris VT,Benavides F,Conti C,Merani S,Lanari C. Cytogenetic findings. Trp53 mutations, and hormone responsiveness in a medroxyprogesterone acetate induced murine breast cancer model. Cancer Genet Cytogenet 2005; 161: 130–9.
- 22 Sartorius CA,Groshong SD,Miller LA,Powell RL,Tung L,Takimoto GS,Horwitz KB. New T47D breast cancer cell lines for the independent study of progesterone B- and A-receptors: only antiprogestin-occupied B- receptors are switched to transcriptional agonists by cAMP. Cancer Res 1994; 54: 3868–77.
- 23 St Bernard R,Zheng L,Liu W,Winer D,Asa SL,Ezzat S. Fibroblast growth factor receptors as molecular targets in thyroid carcinoma. Endocrinology 2005; 146: 1145–53.
- 24 Vanzulli SI,Soldati R,Meiss R,Colombo L,Molinolo AA,Lanari C. Estrogen or antiprogestin treatment induces complete regression of pulmonary and axillary metastases in an experimental model of breast cancer progression. Carcinogenesis 2005; 26: 1055–63.
- 25 Mohammadi M,Froum S,Hamby JM,Schroeder MC,Panek RL,Lu GH,Eliseenkova AV,Green D,Schlessinger J,Hubbard SR. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J 1998; 17: 5896–904.
- 26 Nakayama T,Mutsuga N,Tosato G. Effect of fibroblast growth factor 2 on stromal cell-derived factor 1 production by bone marrow stromal cells and hematopoiesis. J Natl Cancer Inst 2007; 99: 223–35.
- 27 Helguero LA,Viegas M,Asaithamby A,Shyamala G,Lanari C,Molinolo AA. Progesterone receptor expression in medroxyprogesterone acetate-induced murine mammary carcinomas and response to endocrine treatment. Breast Cancer Res Treat 2003; 79: 379–90.
- 28 Labriola L,Salatino M,Proietti CJ,Pecci A,Coso OA,Kornblihtt AR,Charreau EH,Elizalde PV. Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. Mol Cell Biol 2003; 23: 1095–111.
- 29 Boonyaratanakornkit V,McGowan E,Sherman L,Mancini MA,Cheskis BJ,Edwards DP. The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Mol Endocrinol 2007; 21: 359–75.
- 30 Simian M,Molinolo A,Lanari C. Involvement of matrix metalloproteinase activity in hormone-induced mammary tumor regression. Am J Pathol 2006; 168: 270–9.
- 31 Clemm DL,Sherman L,Boonyaratanakornkit V,Schrader WT,Weigel NL,Edwards DP. Differential hormone-dependent phosphorylation of progesterone receptor A and B forms revealed by a phosphoserine site-specific monoclonal antibody. Mol Endocrinol 2000; 14: 52–65.
- 32 Pierson-Mullany LK,Lange CA. Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2. Mol Cell Biol 2004; 24: 10542–57.
- 33 Shekhar MP,Santner S,Carolin KA,Tait L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am J Pathol 2007; 170: 1546–60.
- 34 Shafie SM,Grantham FH. Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 1981; 67: 51–6.
- 35 Lamb CA,Fabris V,Gorostiaga MA,Helguero LA,Efeyan A,Bottino MC,Simian M,Soldati R,Sanjuan N,Molinolo A,Lanari C. Isolation of a stromal cell line from an early passage of a mouse mammary tumor line: a model for stromal parenchymal interactions. J Cell Physiol 2005; 202: 672–82.
- 36 Sadlonova A,Novak Z,Johnson MR,Bowe DB,Gault SR,Page GP,Thottassery JV,Welch DR,Frost AR Breast fibroblasts modulate epithelial cell proliferation in three-dimensional in vitro co-culture. Breast Cancer Res 2005; 7: R46–59.
- 37 Dailey L,Ambrosetti D,Mansukhani A,Basilico C. Mechanisms underlying differential responses to FGF signaling. Cytokine Growth Factor Rev 2005; 16: 233–47.
- 38 Linder C,Bystrom P,Engel G,Auer G,Aspenblad U,Strander H,Linder S. Correlation between basic fibroblast growth factor immunostaining of stromal cells and stromelysin-3 mRNA expression in human breast carcinoma. Br J Cancer 1998; 77: 941–5.
- 39 Hunter DJ,Kraft P,Jacobs KB,Cox DG,Yeager M,Hankinson SE,Wacholder S,Wang Z,Welch R,Hutchinson A,Wang J,Yu K, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007; 39: 870–4.
- 40 Schmahl J,Kim Y,Colvin JS,Ornitz DM,Capel B. Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination. Development 2004; 131: 3627–36.
- 41 Prudovsky I,Savion N,Zhan X,Friesel R,Xu J,Hou J,McKeehan WL,Maciag T. Intact and functional fibroblast growth factor (FGF) receptor-1 trafficks near the nucleus in response to FGF-1. J Biol Chem 1994; 269: 31720–4.
- 42 Marti U,Ruchti C,Kampf J,Thomas GA,Williams ED,Peter HJ,Gerber H,Burgi U. Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues. Thyroid 2001; 11: 137–45.
- 43 Coleman-Krnacik S,Rosen JM. Differential temporal and spatial gene expression of fibroblast growth factor family members during mouse mammary gland development. Mol Endocrinol 1994; 8: 218–29.
- 44 Chodosh LA,Gardner HP,Rajan JV,Stairs DB,Marquis ST,Leder PA. Protein kinase expression during murine mammary development. Dev Biol 2000; 219: 259–76.
- 45 Jackson D,Bresnick J,Rosewell I,Crafton T,Poulsom R,Stamp G,Dickson C Fibroblast growth factor receptor signalling has a role in lobuloalveolar development of the mammary gland. J Cell Sci 1997; 110 (Part 11): 1261–68.
- 46 Pal M,Moffa A,Sreekumar A,Ethier SP,Barder TJ,Chinnaiyan A,Lubman DM. Differential phosphoprotein mapping in cancer cells using protein microarrays produced from 2-D liquid fractionation. Anal Chem 2006; 78: 702–10.
- 47 Qiu M,Olsen A,Faivre E,Horwitz KB,Lange CA. Mitogen activated protein kinase regulates nuclear association of human progesterone receptors. Mol Endocrinol 2003; 17: 628–42.
- 48 Su G,Blaine SA,Qiao D,Friedl A. Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation. J Biol Chem 2007; 282: 14906–15.
- 49 Ross RK,Paganini-Hill A,Wan PC,Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000; 92: 328–32.
- 50 Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321–33.
- 51 Aupperlee M,Kariagina A,Osuch J,Haslam SZ. Progestins and breast cancer. Breast Dis 2005; 24: 37–57.
- 52 Poole AJ,Li Y,Kim Y,Lin SC,Lee WH,Lee EY. Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 2006; 314: 1467–70.
Citing Literature
