Regulation of cell growth of a progestin-dependent murine mammary carcinoma in vitro: progesterone receptor involvement in serum or growth factor-induced cell proliferation

Lamb, Caroline A.; Simian, Marina; Molinolo, Alfredo A.; Pazos, Patricia; Lanari, Claudia

doi:10.1016/s0960-0760(99)00108-9

Cited by 31 publications

(38 citation statements)

References 29 publications

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“…Tumor validation was carried out by cytogenetic analysis (2). Primary cultures and cell proliferation assays were carried out as previously described (18).…”

Section: Tumorsmentioning

confidence: 99%

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

et al. 2011

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Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/ STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment. Cancer Res; 71(10); 3720-31. Ó2011 AACR.

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“…Tumor validation was carried out by cytogenetic analysis (2). Primary cultures and cell proliferation assays were carried out as previously described (18).…”

Section: Tumorsmentioning

confidence: 99%

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

et al. 2011

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“…At that time, the concepts of 'ligand-independent activation' and 'crosstalk' were gaining acceptance and Edwards et al (1993) had suggested that PR could be activated by cAMP analogues. FGFs were the only ones of a series of growth factors tested that stimulated cell proliferation like MPA (Lamb et al 1999). Using different anti-progestins and asPR, we demonstrated that FGFs stimulated cell proliferation via the PR pathway (Lanari et al 1997).…”

Section: Pr Key Player Mediating Cell Proliferationmentioning

confidence: 93%

“…E 2 exerted an inhibitory effect even at low concentrations (Dran et al 1995, Lamb et al 2003. The anti-progestins, RU486, and ZK 98299 (Lamb et al 1999), exerted a striking inhibitory effect, while the antiandrogen hydroxyflutamide had no effect. The inhibitory effect of RU486 was observed at concentrations as low as 10 nM.…”

Section: In Vitro Studies Primary Culturesmentioning

confidence: 93%

“…TGFb 1-3 were all inhibitory (Viegas et al 1999). Interestingly, serum from MPA-treated ovx mice stimulated cell proliferation to levels higher than that from ovx mice, to which MPA was added exogenously, indicating that other serum factors in addition to MPA are participating in tumor growth (Lamb et al 1999). These results are in agreement with data reported in T47D-YB cells in which progestins, in addition to inducing cell proliferation, also stimulate the production of soluble factors that would be responsible for the sustained MAPK signaling leading to cell growth (Faivre & Lange 2007).…”

Section: In Vitro Studies Primary Culturesmentioning

confidence: 99%

“…As for the growth factors, EGF, IGF-I or IGF-II, they exerted almost no stimulatory effect when administered alone (Elizalde et al 1998; however, IGF-I increased MPA-induced cell proliferation. On the other hand, FGFs and HRG exerted a stimulatory effect on MPA-treated or -untreated cells (Lanari et al 1997, Balana et al 1999, Lamb et al 1999. TGFb 1-3 were all inhibitory (Viegas et al 1999).…”

Section: In Vitro Studies Primary Culturesmentioning

confidence: 99%

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The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Lanari¹,

Lamb²,

Fabris³

et al. 2009

Endocrine-Related Cancer

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101

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More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). By contrast, most of the spontaneous, chemically or mouse mammary tumor virus induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependence, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discuss the relevance of this model in comparison with other presently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.

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Carcinoma‐associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: A role for the FGF‐2/FGFR‐2 axis

Giulianelli

Cerliani

Lamb

et al. 2008

Intl Journal of Cancer

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115

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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.

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Regulation of cell growth of a progestin-dependent murine mammary carcinoma in vitro: progesterone receptor involvement in serum or growth factor-induced cell proliferation

Cited by 31 publications

References 29 publications

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

Interaction between FGFR-2, STAT5, and Progesterone Receptors in Breast Cancer

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Carcinoma‐associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: A role for the FGF‐2/FGFR‐2 axis

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