Mammary differentiation induces expression of Tristetraprolin, a tumor suppressor AU-rich mRNA-binding protein

• Published in: Breast cancer research and treatment Vol. 135; no. 3; pp. 749 - 758
• Main Authors: Goddio, M. Victoria, Gattelli, Albana, Slomiansky, Victoria, Lacunza, Ezequiel, Gingerich, Timothy, Tocci, Johanna M., Facchinetti, María M., Curino, Alejandro C., LaMarre, Jonathan, Abba, Martín C., Kordon, Edith C.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.10.2012; Springer; Springer Nature B.V
• Subjects: Analysis; Animal reproduction; Animals; Base Sequence; Benign; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer research; Cancer therapies; Carcinoma; Cell Differentiation; Cell Line, Tumor; Cytokines; Data processing; Differentiation; DNA; DNA microarrays; Female; Gene expression; Gene Expression Regulation, Neoplastic; Glands; Gynecology. Andrology. Obstetrics; Hormones; Humans; Inflammation; Invasiveness; Lactation; Mammary gland; Mammary gland diseases; Mammary Glands, Animal - cytology; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - metabolism; Mammary Glands, Human - metabolism; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Medical sciences; Medicine; Medicine & Public Health; Messenger RNA; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Oncology; Physiological aspects; Pituitary hormones; Preclinical Study; Pregnancy; Prolactin; Prolactin - pharmacology; Protein binding; Proteins; RNA-binding protein; Serial analysis of gene expression; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Transcription; Tristetraprolin - genetics; Tristetraprolin - metabolism; Tumor cells; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Tristetraprolin; Breast cancer; Mammary gland; Lactation; Prolactin; Breast disease; Malignant tumor; Breast feeding; Cell differentiation; Gene expression; Mammary gland diseases; Binding protein; Messenger RNA; Adenohypophyseal hormone; Differentiation; Cancer; Tumor suppressor gene
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-012-2216-0

Tristetraprolin (TTP) is a RNA-binding protein that inhibits the expression of pro-inflammatory cytokines and invasiveness-associated genes. TTP levels are decreased in many different cancer types and it has been proposed that this protein could be used as a prognostic factor in breast cancer. Here, using publicly available DNA microarray datasets, “serial analysis of gene expression” libraries and qRT-PCR analysis, we determined that TTP mRNA is present in normal breast cells and its levels are significantly decreased in all breast cancer subtypes. In addition, by immunostaining, we found that TTP expression is higher in normal breast tissue and benign lesions than in infiltrating carcinomas. Among these, lower grade tumors showed increased TTP expression compared to higher grade cancers. Therefore, these data indicate that TTP protein levels would provide a better negative correlation with breast cancer invasiveness than TTP transcript levels. In mice, we found that TTP mRNA and protein expression is also diminished in mammary tumors. Interestingly, a strong positive association of TTP expression and mammary differentiation was identified in normal and tumor cells. In fact, TTP expression is highly increased during lactation, showing good correlation with various mammary differentiation factors. TTP expression was also induced in mammary HC11 cells treated with lactogenic hormones, mainly by prolactin, through Stat5A activation. The effect of this hormone was highly dependent on mammary differentiation status, as prolactin was unable to elicit a similar response in proliferating or neoplastic mammary cells. In summary, these studies show that TTP expression is strongly linked to the mammary differentiation program in human and mice, suggesting that this protein might play specific and relevant roles in the normal physiology of the gland.