Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation

Salatino, Mariana; Béguelin, Wendy; Peters, María Giselle; Carnevale, Romina P.; Proietti, Cecilia J.; Galigniana, Mario D.; Vedoy, Cleber Giovane; Schillaci, Roxana; Charreau, Eduardo H.; Sogayar, Mari Cleide; Elizalde, Patricia V.

doi:10.1038/sj.onc.1209757

Cited by 43 publications

(34 citation statements)

References 65 publications

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“…Caveolin-1 functions as a molecular switch for some of the extranuclear actions of sex steroids, and progesterone is able to regulate this protein (Salatino et al 2006, Sotgia et al 2006. It would thus be interesting to clarify the role of caveolin-1 in progesterone-associated breast cancer cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

Goglia²,

Sanchez³

et al. 2010

Endocrine-Related Cancer

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While progesterone plays multiple roles in the process of breast development and differentiation, its role in breast cancer is less understood. We have shown previously that progestins stimulate breast cancer cell migration and invasion because of the activation of rapid signaling cascades leading to modifications in the actin cytoskeleton and cell membrane that are required for cell movement. In this study, we have investigated the effects of progesterone on the formation of focal adhesion (FA) complexes, which provide anchoring sites for cell attachment to the extracellular matrix during cell movement and invasion. In T47-D breast cancer cells, progesterone rapidly enhances FA kinase (FAK) phosphorylation at Tyr 397 in a time-and concentration-dependent manner. As a result, exposure to progesterone leads to increased formation of FA complexes within specialized cell membrane protrusions. The cascade of events required for this phenomenon involves progesterone receptor interaction with the tyrosine kinase c-Src, which activates the phosphatidylinositol-3-kinase/Akt pathway and the small GTPase RhoA/Rho-associated kinase complex. In the presence of progesterone, T47-D breast cancer cells display enhanced horizontal migration and invasion of three-dimensional matrices, which is reversed by small interfering RNAs abrogating FAK. In conclusion, progesterone promotes breast cancer cell movement and invasion by facilitating the formation of FA complexes via the rapid regulation of FAK. These results provide novel mechanistic views on the effects of progesterone on breast cancer progression, and may in the future be helpful to develop new strategies for the treatment of endocrine-sensitive breast cancers.

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Section: Discussionmentioning

confidence: 99%

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

Goglia²,

Sanchez³

et al. 2010

Endocrine-Related Cancer

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“…Separately, several groups have demonstrated that P induces the expression and phosphorylation of STAT3 and STAT5 (Richer et al 1998, Proietti et al 2005, where P-induced activation of Jak1 and Jak2 and phosphorylation of STAT1 and STAT3 is Src dependent (Zhang et al 2000, Proietti et al 2005. More recently, c-Src was shown to phosphorylate P-induced caveolin-1 that mediates a proliferative effect of P on mammary tumor cells (Salatino et al 2006). Although several groups have implicated the MAP and PI3 kinases as downstream effectors of crosstalk between PR and c-Src (Lange 2004), our present results indicate that these pathways do not participate in the synergistic effect of PC PRL on the MMTV-LTR.…”

Section: Discussionmentioning

confidence: 99%

A 5′ distal palindrome within the mouse mammary tumor virus-long terminal repeat recruits a mammary gland-specific complex and is required for a synergistic response to progesterone plus prolactin

Morabito¹,

Trott²,

Korz³

et al. 2008

Journal of Molecular Endocrinology

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Progesterone (P) and prolactin (PRL) fulfill crucial roles during growth and differentiation of the mammary epithelium, and each has been implicated in the pathogenesis of mammary cancer. We previously identified that these hormones synergistically stimulate the proliferation of mouse mammary epithelial cells in vivo, although the mechanism(s) underlying their cooperative effect are unknown. We now report a novel pathway by which P and PRL synergize to activate transcription from the long terminal repeat (LTR) of the mouse mammary tumor virus-LTR (MMTV-LTR) in T47D breast cancer cells. Using serial 5 0 and 3 0 deletions of the MMTV-LTR, in addition to selective mutations, we identified that a previously uncharacterized inverted palindrome on the distal enhancer (K941/K930), in addition to a signal transducer and activator of transcription 5 site, was essential for the synergistic activation of transcription by P and PRL. Notably, hormone synergy occurred via a mechanism that was independent of the P receptor DNA-binding elements found in the proximal MMTV-LTR hormone-response element. The palindrome specifically recruited a protein complex (herein termed mammary gland-specific complex) that was almost exclusive to normal and cancerous mammary cells. The synergy between P and PRL occurred via a Janus kinase 2 and c-Src/Fyn-dependent signaling cascade downstream of P and PRL receptors. Combined, our data outline a novel pathway in T47D cells that may facilitate the action(s) of P and PRL during mammary development and breast cancer.

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“…This antibody has been used and validated previously by our group and by others. 21,23,24 Sections were incubated with LSAB2 (Dakocytomation). 3-3 0 -diaminobenzidine was used for colour development and haematoxylin was used for counterstaining.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Caveolin-1 expression in human breast lobular cancer progression

et al. 2009

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Caveolin-1 is the principal structural protein of caveolae, and caveolin-1 gene plays a role as a tumour suppressor gene in human mammary cancer-derived cells. However, limited data are available concerning caveolin-1 expression in human breast cancer tissue. We evaluated caveolin-1 expression in normal lobular epithelial cells and in the whole human lobular neoplasia spectrum disease, with the aim to examine differences of caveolin-1 expression in human lobular neoplasia progression. We selected 147 cases of pure lobular lesions, ie lobular intraepithelial neoplasia and invasive lobular carcinoma, from 112 patients. Presence of caveolin-1 was evaluated by immunohistochemistry. Among 81 lobular intraepithelial neoplasia lesions studied, 43% were associated with invasive lobular carcinoma, with positive correlation between lobular intraepithelial neoplasia grade and presence of invasive component (P ¼ 0.01). In total, 64% of lobular lesions were positive for caveolin-1 (81% lobular intraepithelial neoplasia and 42% invasive lobular carcinoma), and a significant difference in terms of caveolin-1 expression was present between lobular intraepithelial neoplasia and invasive lobular carcinoma (P ¼ 0.0001). Variations in caveolin-1 expression were evident among the different lobular intraepithelial neoplasia grades (91% grade 1, 68% grade 2, 35% grade 3); the difference was significant comparing lobular intraepithelial neoplasia grade 3 vs 1 (P ¼ 0.0001) and grade 3 vs 2 (P ¼ 0.007) but not grade 1 vs 2. Furthermore, significant differences were found between lobular intraepithelial neoplasia grades 1 and 2 vs invasive lobular carcinoma (P ¼ 0.0001), but not between lobular intraepithelial neoplasia grade 3 and invasive lobular carcinoma (P ¼ 0.196). In conclusion, variations of caveolin-1 expression may have an important role in the progression of human breast lobular cancer; in addition, they confirm the powerful clinical impact of the lobular intraepithelial neoplasia classification for lobular intraepithelial neoplasia, supporting the direct origin of invasive lobular carcinoma from clonal expansion of the lobular intraepithelial neoplasia lesions cells.

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Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation

Cited by 43 publications

References 65 publications

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

Progesterone receptor enhances breast cancer cell motility and invasion via extranuclear activation of focal adhesion kinase

A 5′ distal palindrome within the mouse mammary tumor virus-long terminal repeat recruits a mammary gland-specific complex and is required for a synergistic response to progesterone plus prolactin

Caveolin-1 expression in human breast lobular cancer progression

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