Abstract


The ovarian steroid hormones estrogen (E) and progesterone (P) play vital roles in the development of the normal mammary gland and are likewise linked to mammary carcinogenesis via their receptors. Progesterone receptor (PR) is expressed as two isoforms, PRA and PRB. In human breast tumors the expression ratio of PRA/PRB had been found to be altered and the overexpression of either the A or B form is suggested to have distinct clinical implications. view more

The ovarian steroid hormones estrogen (E) and progesterone (P) play vital roles in the development of the normal mammary gland and are likewise linked to mammary carcinogenesis via their receptors. Progesterone receptor (PR) is expressed as two isoforms, PRA and PRB. In human breast tumors the expression ratio of PRA/PRB had been found to be altered and the overexpression of either the A or B form is suggested to have distinct clinical implications. To further study the role of PR isoforms on mammary gland biology and preneoplasia, transgenic mice carrying either an additional A (PRA) or  B (PRB) form of PR were generated (Shyamala, 1998; Simian, 2009). Both mice strains present abnormal mammary gland development;  overexpression of the A isoform of PR leads to increased side branching and multilayered ducts, while overexpressing the B isoform leads to limited ductal growth. PR signaling has been shown to play a major role in the  maintenance of the stem cell population in the mammary gland. However, the role of each isoform on the dynamics of this stem/progenitor cell hierarchy has not been unraveled. We propose that the altered PR A/B ratio affects the expansion and self-renewal of the mammary gland  stem cell population and that E plays a major role in this phenomenon.
Flow cytometry assays revealed that mammary glands derived from PRB mice present a higher percentage of CD29h/CD24+ positive cells (P=0.003), compared to those derived from PRA and WT mice. Additionally, mammosphere-forming capacity was also significantly higher in PRB mammary glands (P=0.0016). To evaluate the role of E and P we analyzed mammary glands of transgenic mice upon ovariectomy (OVX) and found that the percentage of CD29h/CD24+ cells increased in mammary glands derived from OVX WT and PRA mice, compared to their sham controls, while no changes were observed in those derived from OVX PRB mice. Moreover, in vivo treatment with the anti estrogen ICI 182,780 led to an increase in mammosphere forming capacity of cells derived from WT and PRA, but not in PRB mice. Our results suggest that the B isoform of PR may play a predominant role in the maintenance of stem cell population of the mammary gland and in the development of hormone resistance given that ovarian regulation affected mammary glands of WT and PR-A mice, but not PR-B mice.

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