RANKL expression in normal and malignant breast tissue responds to progesterone and is up-regulated during the luteal phase

Springer Science and Business Media LLC - Tập 146 - Trang 515-523 - 2014
Hong Hu1, Jun Wang1, Akash Gupta1, Ali Shidfar1, Daniel Branstetter2, Oukseub Lee1, David Ivancic1, Megan Sullivan3, Robert T. Chatterton4,5, William C. Dougall6, Seema A. Khan1,5
1Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, USA
2Department of Pathology, Amgen Inc., Seattle, USA
3Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, USA
4Department of Obstetrics & Gynecology, Northwestern University Feinberg School of Medicine, Chicago, USA
5Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA
6Therapeutic Innovation Unit, Amgen, Inc, Seattle, USA

Tóm tắt

The receptor activator of nuclear factor-κB ligand (RANKL) acts as a paracrine factor in progesterone-induced mammary epithelial proliferation and tumorigenesis. This evidence comes mainly from mouse models. Our aim was to examine whether RANKL expression in human normal and malignant breast is under the control of progesterone throughout the menstrual cycle. Breast epithelial samples were obtained by random fine needle aspiration (rFNA) of the contralateral unaffected breasts (CUB) of 18 breast cancer patients, with simultaneous serum hormone measurements. Genes correlated with serum progesterone levels were identified through Illumina microarray analysis. Validation was performed using qRT-PCR in rFNA samples from CUB of an additional 53 women and using immunohistochemistry in tissue microarrays of 61 breast cancer samples. Expression of RANKL, DIO2, and MYBPC1 was correlated with serum progesterone in CUB, and was significantly higher in luteal phase. RANKL and MYBPC1 mRNA expression were highly correlated between CUB and matched tumor samples. RANKL protein expression was also significantly increased in the luteal phase and highly correlated with serum progesterone levels in cancer samples, especially in hormone receptor positive tumors. The regulatory effects of progesterone on the expression of RANKL, DIO2, and MYBPC1 were confirmed in three-dimensional cultures of normal breast organoids. In normal breast and in breast cancer, RANKL mRNA and protein expression fluctuate with serum progesterone with highest levels in the luteal phase, suggesting that RANKL is a modulator of progesterone signaling in normal and malignant breast tissue and a potential biomarker of progesterone action and blockade.

Tài liệu tham khảo

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