Adjuvant high-dose medroxyprogesterone acetate for early breast cancer: 13 years update in a multicentre randomized trial

Focan, C.; Beauduin, M.; Salamon, E.; Grève, Jacques De; Wasch, G. De; Lobelle, Jean Pierre; Majois, F.; Tagnon, A.; Tytgat, Jan; Belle, Sebastian; Vandervellen, R; Vindevoghel, A.

doi:10.1054/bjoc.2001.1829

Cited by 18 publications

(10 citation statements)

References 35 publications

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“…The success of these regimens fostered the assumption that progesterone would similarly counteract the proliferative effects of estrogen in breast cancers. Indeed, in the absence of chemotherapy, high-dose MPA increases disease-free and overall survival in node-negative premenopausal patients (39). However, the same study found that MPA therapy led to worse outcomes for node-positive premenopausal patients, suggesting that the success of MPA therapy in breast cancer is context dependent.…”

Section: Discussionmentioning

confidence: 96%

Progestins Initiate a Luminal to Myoepithelial Switch in Estrogen-Dependent Human Breast Tumors without Altering Growth

Sartorius¹,

Harvell²,

Shen³

et al. 2005

Cancer Research

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Although long-term clinical use of progestins is associated with an increased incidence of breast cancers, their role in established cancers is unclear. Estrogens are considered to be the main mitogens in the majority of breast cancers. Whether progesterone affects proliferation and/or differentiation is under debate. To assess the role of progesterone in established breast cancers, we used T47D human breast cancer cells that are estrogen receptor (ER) positive and either progesterone receptor (PR) negative or positive for PRA, PRB, or both. These cells were grown as strictly estrogen-dependent solid tumors in ovariectomized female nude mice. Progesterone or medroxyprogesterone acetate (MPA) alone did not support tumor growth, nor did progesterone or MPA given simultaneously with estrogen significantly alter estrogen-dependent tumor growth. However, treatment of mice bearing ER+PR+ but not ER+PRÀ tumors with either progesterone or MPA increased expression of the myoepithelial cytokeratins (CK) 5 and 6 in a subpopulation of tumor cells. These CK5+/CK6+ cells had decreased expression of luminal epithelial CK8, CK18, and CK19. We conclude that progestins exert differentiative effects on tumors characterized by transition of a cell subpopulation from luminal to myoepithelial. This may not be beneficial, however, because such a phenotype is associated with poor prognosis. (Cancer Res 2005; 65(21): 9779-88)

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Section: Discussionmentioning

confidence: 96%

Progestins Initiate a Luminal to Myoepithelial Switch in Estrogen-Dependent Human Breast Tumors without Altering Growth

Sartorius¹,

Harvell²,

Shen³

et al. 2005

Cancer Research

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“…Furthermore, in agreement with the results presented here, the role of Pg in the induction of apoptosis via induction of NOSII to increase NO levels was shown in ovarian cancer cells, 30 indicating a general function of Pg in this mechanism. In fact, several randomised studies and clinical trials have shown that treatment with progestogens led to significant though modest improvement of the relapse-free survival, 42,43 and that inclusion of progestogens in hormone replacement therapy reduces the risk of recurrence, which is associated with an increase in the apoptosis/proliferation ratio within the tumour. 44 The balance between cell death and cell proliferation determines tumour growth rate and even a small alteration in these parameters can be important for the expansion or regression of malignant tumours.…”

Section: Discussionmentioning

confidence: 99%

Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells

Bentrari

Arnould́

Jackson

et al. 2005

Laboratory Investigation

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The presence of hormone receptors is related to survival outcome in breast cancer. Previous results from our laboratory established a correlation between the presence of nitric oxide synthase II (NOSII) and nitric oxide (NO) production with progesterone receptors in a series of human breast tumours. Furthermore, this was directly related to a lower tumour grade and a lower proliferation rate of the tumour cells. To examine these results in further detail, the effect of progesterone (Pg) and 17b-oestradiol (E2) on NOSII expression was analysed in the human breast cancer cell line MCF-7. By Northern blot and promoter activity, we show that a cytokine mix (TNF-a, IL-b, and IFN-c) induces NOSII transcription after 6 h stimulation. In the absence of cytokines, neither hormone affects NOSII expression. However, Pg but not E2, enhances cytokine-induced NOSII transcription as well as NO synthesis, mainly by cooperation with gamma-interferon. The increase in NO accumulation in the media induced by addition of Pg to the cytokine treatment significantly increases cell death, mainly accounted for by apoptosis, as compared to the effect of cytokines alone. Our findings help clarify the role of steroid hormones in NOSII expression as well as the effect on cell viability and may suggest novel approaches towards hormonotherapy and the treatment of cancer. Keywords: NOSII; progesterone; transcription; breast cancer; apoptosis; nitric oxide Endogenous nitric oxide (NO) is produced in cells by the nitric oxide synthases (NOS), which exist as three isoforms. The calcium-dependent endothelial (eNOS or NOSIII) and neuronal (nNOS or NOSI) enzymes are constitutively present in various cell types and produce low levels of short acting NO. 1 The third isoform (iNOS or NOSII) is induced in most cell types only in response to external stimuli such as bacterial lipopolysaccharides (LPS) or diverse cytokines, and generates high sustained levels of NO. 2 NO is a transcellular messenger that plays an important role in diverse physiological processes such as vascular homeostasis, immunity and neurotransmission. The effect of endogenous NO on cellular homeostasis is highly dependent on the level of its synthesis. Thus, at low levels it can promote cell proliferation and angiogenesis whereas at high concentrations, such as those produced by NOSII, it can lead to cell damage and death. 3 Therefore, it is important to understand the regulation of the NOS enzymes in order to unravel the role of NO in physiological and pathological conditions. So far it is known that expression of NOSII is regulated mainly at the transcriptional level, although additional post-transcriptional and posttranslational controls have been documented. 4 The most important transcription factors required for NOSII expression are nuclear factor kappa B (NFkB) 5 and activator protein 1 (AP-1). 6 These transcription factors are induced or activated by cytokines such as tumour necrosis alpha (TNF-a), interleukin-1beta (IL-1b), gamma interferon (IFN-g) or LPS. 7 However, differenc...

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“…However, two of the older trials that used long-term MPA dosing reported 12-and 13-year follow-up data, and a retrospective subset analysis suggested a benefit in post-menopausal patients. A total of 950 patients were randomized to chemotherapy with or without a six-month course of MPA, given in a one-month induction, five-month maintenance protocol [14, 15]. In both trials, the MPA-treated subsets of patients had improved disease-free survival ( P = 0.01 in one trial; in the other, P = 0.06 for node-negative and P = 0.002 for node-positive patients).…”

Section: Identification and Validation Of Medroxyprogesterone Acetatementioning

confidence: 99%

“…Estrogen combined with MPA was demonstrated to be deleterious in the form of HRT, so it is reasonable that MPA should not be administered to patients that are pre-menopausal. Intriguingly, patient responses were not well-correlated with progesterone receptor expression [14, 16, 17], which suggested that more recent data showing that interaction of MPA with the GR may be relevant.…”

Section: Identification and Validation Of Medroxyprogesterone Acetatementioning

confidence: 99%

Clinical-translational strategies for the elevation of Nm23-H1 metastasis suppressor gene expression

2009

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Interruption of the tumor metastatic process is a new, thought provoking molecular target for the treatment of cancer. The Nm23-H1 metastasis suppressor gene stands as a validated molecular target owing to its reduced expression in many aggressive human tumors, and the reduction in meta-static potential in vivo upon re-expression in multiple cell lines. Several compounds have been identified which elevate Nm23-H1 expression in vitro including indomethacin, γ Linolenic Acid, trichostatin A, 5-aza-deoxycytidine, and high dose medroxyprogesterone acetate. Using a model of lung metastatic colonization by MDA-MB-231 human breast carcinoma cells, we demonstrated that high dose MPA reduced the formation of overt lung metastases by 37–46% and those metastases that formed were statistically smaller. A Phase II clinical trial of high dose MPA, alone or in combination with metronomic chemotherapy has recently opened.

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Adjuvant high-dose medroxyprogesterone acetate for early breast cancer: 13 years update in a multicentre randomized trial

Cited by 18 publications

References 35 publications

Progestins Initiate a Luminal to Myoepithelial Switch in Estrogen-Dependent Human Breast Tumors without Altering Growth

Progestins Initiate a Luminal to Myoepithelial Switch in Estrogen-Dependent Human Breast Tumors without Altering Growth

Progesterone enhances cytokine-stimulated nitric oxide synthase II expression and cell death in human breast cancer cells

Clinical-translational strategies for the elevation of Nm23-H1 metastasis suppressor gene expression

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