Progestin-induced fatty acid synthetase in human mammary tumors: From molecular to clinical studies

Chalbos, Dany; Joyeux, Christian; Galtier, Florence; Rochefort, Henri

doi:10.1016/0960-0760(92)90211-z

Cited by 26 publications

(19 citation statements)

References 23 publications

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“…7A). Moreover, concurring with previous data (16,35), progesterone increased the expression of FAS and ALP, which are markers of differentiation correlating with lipid storage in breast cancer cells (9,15) (Fig. 7B).…”

Section: Resultssupporting

confidence: 80%

TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone

Gizard

Robillard

Gross

et al. 2006

Molecular and Cellular Biology

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The sex steroid progesterone is essential for the proliferation and differentiation of the mammary gland epithelium during pregnancy. In relation to this, in vitro studies using breast carcinoma T47D cells have demonstrated a biphasic progesterone response, consisting of an initial proliferative burst followed by a sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the progesterone effects on mammary cell growth and differentiation remain to be determined. The steroid hormones estrogen and progesterone play key roles in the growth of the mammary gland (49). Estrogens appear to be the main drive for proliferation of the mammary gland epithelium, whereas progesterone is required for its terminal growth and differentiation (27). The induction of mammary epithelial development during pregnancy is mediated by a rise in progesterone levels (51). The physiological effects of progesterone occur mainly via interaction with specific intracellular progesterone receptors (PRs), PR-A and PR-B, which are products of a single gene and members of the nuclear receptor (NR) family (11). Studies performed on mice in which the expression of both PRs was ablated have demonstrated that progesterone is necessary for ductal branching and the lobulo-alveolar development of the mammary gland (45). More recently, selective ablation of each receptor isoform has indicated that PR-B is specifically required for the progesterone-dependent development of the mammary gland during pregnancy (11).In relation to the function of progesterone in breast development, both growth-stimulatory and -inhibitory effects have been previously reported on breast epithelium cells and cancer development in tumor animal models (11,42,46). Moreover, in vitro studies using the PR-positive mammary carcinoma T47D cell line as a model have demonstrated a biphasic cellular response to either progesterone or its derivatives (R5020 or ORG 2058), with an immediate proliferative burst followed by a sustained growth arrest (28,38,50). As with many hormones and growth factors, the regulation of retinoblastoma gene product (pRB) phosphorylation-a critical checkpoint of the G 1 /S transition-plays a major role in the control of proliferation by progesterone (18,39,71). The initial pRB phosphorylation provoked by progesterone is catalyzed by constitutively expressed cyclin-dependent kinases (CDKs), which are activated through interaction with specific cyclins induced by progesterone (39). The ensuing growth arrest is associated, at least in part, with the transitory induction of the cyclin-dependent kinase inhibitors (CDKIs) p21Cip1/WAF1 (p21) and p18 INK4c(p18), followed by a sustained induction of p27 Kip1 (p27) (28,

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Section: Resultssupporting

confidence: 80%

TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone

Gizard

Robillard

Gross

et al. 2006

Molecular and Cellular Biology

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“…This was clearly visible for samples treated either with estradiol and OH-Tam, in which pS2 mRNA level was induced fourfold, or with estradiol, OH-Tam and IGFI, in which pS2 mRNA level was induced eightfold. Since these results were comparable to those previously described in MCF7 cells (Chalbos et al, 1992), we did not investigate the e ect of the di erent treatments on cathepsin D gene expression. The e ect of IGFI treatment on DNase I hypersensitivity of the pS2 and cathepsin D genes 5'-¯anking sequences in MCF7 cells, grown in serum-deprived medium was then investigated.…”

Section: Resultssupporting

confidence: 74%

Chromatin structure of the regulatory regions of pS2 and cathepsin D genes in hormone-dependent and -independent breast cancer cell lines

et al. 1999

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We have compared the DNase I hypersensitivity of the regulatory region of two estrogen-regulated genes, pS2 and cathepsin D in hormone-dependent and -independent breast carcinoma cell lines. This strategy allowed the identi®cation of two important control regions, one in pS2 and the other in cathepsin D genes. In the hormonedependent MCF7 cell line, within the pS2 gene 5'-anking region, we detected two major DNase I hypersensitive sites, induced by estrogens and/or IGFI: pS2-HS1, located in the proximal promoter and pS2-HS4, located 710.5 Kb from the CAP site, within a region that has not been cloned. The presence of these two DNase I hypersensitive sites correlates with pS2 expression. Interestingly in MCF7 cells, estrogens and IGFI induced indistinguishable chromatin structural changes over the pS2 regulatory region, suggesting that the two transduction-pathways converge to a unique chromatin target. In two cell lines that do not express pS2, MDA MB 231, a hormone-independent cell line that lacks the estrogen receptor a, and HE5, a cell line derived from MDA MB 231 by transfection that expresses estrogen receptor a, there was only one hormoneindependent DNase I hypersensitive site. This site, pS2-HS2, was located immediately upstream of pS2-HS1. In MCF7 cells, two major DNase I hypersensitive sites were present in the 5'-¯anking sequences of the cathepsin D gene, which is regulated by estrogens in these cells. These sites, catD-HS2 and catD-HS3, located at positions 72.3 Kb and 73.45 Kb, respectively, were both hormone-independent. A much weaker site, catD-HS1, covered the proximal promoter. In MDA MB 231 cells, that express cathepsin D constitutively, we detected an additional strong hormoneindependent DNase I hypersensitive site, catD-HS4, located at position 74.3 Kb. This region might control the constitutive over-expression of cathepsin D in hormone-independent breast cancer cells. All together, these data demonstrate that a local reorganization of the chromatin structure over pS2 and cathepsin D promoters accompanies the establishment of the hormone-independent phenotype of the cells.

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“…9 However, in vivo, these progestins increase the incidence of breast cancer in postmenopausal women receiving hormonal replacement therapy compared to women treated only by estrogens. 10,11 We previously showed that FAS was induced specifically by these progestins via the PR and some growth factors but not through the ER, but both in breast cancer cell lines [12][13][14] and in vivo. 14,15 Others have then reported that FAS was overexpressed in breast cancer of poor prognosis, 16 and that its inhibition was efficient to decrease the growth of mammary tumors in rodents.…”

mentioning

confidence: 99%

“…10,11 We previously showed that FAS was induced specifically by these progestins via the PR and some growth factors but not through the ER, but both in breast cancer cell lines [12][13][14] and in vivo. 14,15 Others have then reported that FAS was overexpressed in breast cancer of poor prognosis, 16 and that its inhibition was efficient to decrease the growth of mammary tumors in rodents. 17 In a first attempt to specify at which steps these progestins might be acting in human mammary carcinogenesis, we now evaluate the expression of PR and FAS in early steps of carcinogenesis.…”

mentioning

confidence: 99%

Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis

Esslimani-Sahla

Thézenas²,

Simony-Lafontaine

et al. 2006

Intl Journal of Cancer

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Progestins increase the risk of breast cancer in the hormone therapy of menopause, and progesterone receptor-induced fatty acid synthase (FAS) is a potential therapeutical target of breast cancer. In a first attempt to specify in which lesions at risk of breast cancer progestins might be acting, we have compared the progesterone receptor (PR) and FAS expression in preinvasive breast lesions and in adjacent ''normal'' mammary glands. We used archive paraffin-embedded tissues from 116 patients, with 164 lesions of increasing histological risk from nonproliferative ''benign'' breast disease (BBD) to in situ breast carcinomas. Immunostaining using our FAS antibody and a PR antibody from Dako was quantified as continuous variables by computer-assisted image analysis. FAS level increased (p < 10 23 by the KruskallWallis test) in all lesions, starting from nonproliferative BBD, and was maximal in in situ carcinoma. The % of PR-positive cells increased from nonproliferative BBD and was higher in proliferative atypia (p < 10 23 ). It was very low in high-grade DCIS corresponding to a likely different carcinogenesis pathway. There was a trend for a positive correlation between FAS and PR in normal glands. However, the 2 markers increased independently in BBD and were negatively correlated in in situ carcinomas. FAS and PR were positively correlated with Ki67 in BBD. The increased PR level in premalignant steps of mammary carcinogenesis suggests an early increased responsiveness to progestins. The increased FAS expression, in lesions parallel to their increased breast cancer risk, suggests further studies to develop new markers of high-risk lesions and to prevent breast cancer. ' 2006 Wiley-Liss, Inc.

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Progestin-induced fatty acid synthetase in human mammary tumors: From molecular to clinical studies

Cited by 26 publications

References 23 publications

TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone

TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone

Chromatin structure of the regulatory regions of pS2 and cathepsin D genes in hormone-dependent and -independent breast cancer cell lines

Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis

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