Role of HCG and Inhibin in Breast-Cancer (Review)

Ih, Russo; Russo, José

doi:10.3892/ijo.4.2.297

Cited by 25 publications

(30 citation statements)

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“…PI-MEC can function as alveolar progenitors in subsequent pregnancies, and it is thought that they would be related to differences in response to hormonal stimulation and carcinogenic agents observed between nulliparous and parous females (Wagner et al 2002, Henry et al 2004, Boulanger et al 2005. Several authors have focused on finding molecular changes as a mechanism of the pregnancy-induced protection (Russo & Russo 1994, Ginger et al 2001, Sivaraman et al 2001, D'Cruz et al 2002, Ginger & Rosen 2003, Medina & Kittrell 2003, Medina 2004. These changes in the genomic signature induced by physiological process like pregnancy have significant relevance with the novel observation from our studies relating that prenatal exposure to low and high doses of BPA induced differences in the gene expression of the mammary glands, which were time-and dose specific.…”

Section: Discussionmentioning

confidence: 99%

Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature

Moral

Wang²,

Russo³

et al. 2007

Journal of Endocrinology

147

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Bisphenol A (BPA), known as an environmental endocrine disruptor, is widely used as a plasticizer. This study aims to investigate whether exposure in utero to BPA alters the architecture, proliferative index, and genomic signature of the rat mammary gland during critical stages of development. Pregnant rats were gavaged with 25 mg BPA/kg body weight (BW; low-dose group) or 250 mg BPA/kg BW (high-dose group) from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50, and 100 days, and mammary glands were collected. Analysis of gland morphology was performed from whole-mounted mammary tissue, while proliferative index was determined by detection of bromodeoxyuridine incorporation in the epithelial cells. Genomic profiles were obtained by microarray analysis, and some genes were validated by real-time RT-PCR. BPA exposure induced changes in the mammary gland that were time and dose specific. High-dose exposure resulted in architectural modifications, mainly in the number of undifferentiated epithelial structures of the breast tissue. Proliferative index did not show remarkable differences by the effect of BPA. Low and high doses of BPA changed the gene expression signature of the mammary gland following a different fashion: low dose had the highest effect by 50 days, while high dose had a highest influence on gene expression by 100 days. Both doses presented a significant cluster of up-modulated genes related to the immune system at the age of maximal changes. Moreover, high-dose exposure induced changes in genes related to differentiation suggesting alterations in the normal development of the gland. The increase of undifferentiated structures and the changes in the gene expression profile at different ages suggest that prenatal exposure to BPA can affect the susceptibility of the mammary gland to transformation.

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Section: Discussionmentioning

confidence: 99%

Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature

Moral

Wang²,

Russo³

et al. 2007

Journal of Endocrinology

147

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“…This fact may explain the low mean values of hCG-mRNA copy numbers in our study (mean of breast carcinomas: 68 copies per 200 ng total RNA; mean of fibroadenomas: 85 copies). Russo & Russo (1994) showed that hCG was able to induce a protective effect on rat mammary carcinogenesis and that the effect was dose dependent. After carcinogen administration, rats treated with hCG developed both benign and malignant tumours, but their incidence and the number of tumours per animal were significantly decreased by hormonal treatment.…”

Section: Discussionmentioning

confidence: 99%

Human chorionic gonadotrophin-beta transcripts correlate with progesterone receptor values in breast carcinomas

Reimer¹,

Koczan²,

Müller³

et al. 2000

Journal of Molecular Endocrinology

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The pathophysiological role for the expression of human chorionic gonadotrophin (hCG) in malignant neoplasms is currently speculative. We investigated the overall expression of genes hCG-5, 3, 8 and 7 in breast carcinoma (n=214), fibroadenoma (n=37) and macromastia (n=10) by quantitative reverse transcriptase-PCR. Eighty (37·4%) of the breast cancer samples revealed positive hCG-mRNA expression and the mean value was 67·9 copies per 200 ng total RNA (range: 0-1743; 95% confidence interval (CI) for mean: 44-92). Fibroadenomas had more frequently detected (56·8%) and greater hCG-copy numbers (mean 86·9; range: 0-845; 95% CI for mean: 35-138). Macromastia probes yielded no positive hCG-mRNA. The hCG-mRNA expression was significantly different in the three histological subgroups (P=0·006). Among breast carcinomas, a positive correlation was detected between hCGmRNA copy numbers and progesterone receptor (PgR) values (P<0·001). No significant differences were seen regarding disease-free (P=0·87) and overall survival (P=0·20) depending on hCGmRNA status. Finally, our findings do not support a role for hCG-in malignant transformation of human breast cells and indicate a possible involvement of hCG-in benign breast disease. The relationship with PgR expression may suggest that progestins regulate the expression of hCG in breast epithelial cells.

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“…This finding is not surprising because the two stages have diametrically opposed cell fates and are structurally, hormonally, and functionally distinct. The developing mammary gland is primarily composed of ductal epithelium proliferating under the influence of estrogen and progesterone, whereas involuting mammary gland is lobulo-alveolar epithelium undergoing apoptosis initiated by prolactin withdrawal (37,38). The marked differences at these stages likely account for the disparate effects of IGF-II on PTEN.…”

Section: Igf-ii Effect Is Epithelial Cell Autonomous-bothmentioning

confidence: 99%

Insulin-like Growth Factor-II Regulates PTEN Expression in the Mammary Gland

Moorehead

Hojilla

Belle

et al. 2003

Journal of Biological Chemistry

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The tumor suppressor PTEN is altered in many cancers, including breast cancer, but only a handful of factors are known to control its expression. PTEN plays a vital role in cell survival and proliferation by regulating Akt phosphorylation, a key component of the phosphatidylinositol 3 kinase (PI3K) pathway. Here we show that insulin-like growth factor-II (IGF-II), which signals through PI3K, regulates PTEN expression in the mammary gland. IGF-II injection into mouse mammary gland significantly increased PTEN expression. Transgenic IGF-II expression also increased mammary PTEN protein, leading to reductions in Akt phosphorylation, epithelial proliferation, and mammary morphogenesis. IGF-II induced PTEN promoter activity and protein levels and this involved the immediate early gene egr-1. Thus, we have identified a novel negative feedback loop within the PI3K pathway where IGF-II induces PTEN expression to modulate its physiologic effects.PTEN 1 is emerging as the most frequently altered tumor suppressor gene other than p53 (1). PTEN is mutated in Cowden's syndrome, a condition of familial cancer predisposition, and is frequently altered in a variety of spontaneous cancers including breast cancers (2-4). The loss of even one PTEN allele in mice leads to a high incidence of tumors in a variety of tissues (3,5). Breast cancer in humans is associated with a loss of heterozygosity or mutation of the PTEN gene, and decreased PTEN expression has been associated with invasive breast cancer and poor prognosis (2, 6, 7). The principal activity of PTEN is to dephosphorylate a phospholipid second messenger, phosphatidylinositol 3,4,5-triphosphate (PIP3), produced by phosphatidylinositol 3 kinase (PI3K) (8, 9). PIP3 is the major activator of the cell survival kinase Akt (8, 9). Thus, negative regulation of the PI3K pathway by PTEN is critical, and the loss of PTEN function creates an environment conducive to tumorigenesis.Despite the obvious importance of PTEN, only a handful of molecules are known to control its expression. Intracellular molecules reported to regulate PTEN transcription include p53 (10), peroxisome proliferator-activated receptor ␥ (11) and Egr-1 (12). These proteins induce PTEN promoter activity and putative binding sites for each have been identified in the PTEN promoter. Transforming growth factor ␤ and progesterone have also been proposed to alter PTEN expression. Transforming growth factor ␤ inhibited PTEN expression, but the nature of this regulation is unknown (13). Endometrial PTEN levels were higher during the secretory compared with the proliferative phase of the menstrual cycle implying an association with progesterone levels (14). Given the critical role of PTEN in the control of cell survival and proliferation, it stands to reason that extracellular factors such as hormones or growth factors should also influence PTEN expression.Insulin-like growth factors (IGFs) are potent mitogens that impact development, are implicated as risk factors in breast cancer, and are overexpressed in human cancers (...

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Role of HCG and Inhibin in Breast-Cancer (Review)

Cited by 25 publications

References 0 publications

Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature

Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature

Human chorionic gonadotrophin-beta transcripts correlate with progesterone receptor values in breast carcinomas

Insulin-like Growth Factor-II Regulates PTEN Expression in the Mammary Gland

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