Abstract 2240: Progesterone receptor isoform ratio regulates the stem cell population in the mouse mammary gland
Authors: Recouvreux Maria S. , Sampayo Rocio , Simian Marina 
Published: August 2015

The ovarian steroid hormones progesterone and estrogen play vital roles in the development of normal mammary gland and are likewise linked to mammary carcinogenesis via their receptors. Progesterone receptor (PR) is expressed as two isoforms, PR-A and PR-B, both in human and mouse. It has been reported that in human breast tumors the PR-A/PR-B expression ratio is altered. To further study the role of PR isoforms on mammary gland biology, transgenic mice carrying either an additional A form of PR (PR-A) or the B form of PR (PR-B) were generated. Both mice strains present abnormal development in their mammary glands. 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. The characteristics of mammary glands from these mice provide direct evidence that an aberration in the mechanisms regulating the differential expression of the two isoforms of PR can have major implications to mammary carcinogenesis and might affect the stem cell population of the gland.

Recent studies have shown that a hierarchy of mammary stem/progenitor cells exists among the mammary epithelium in both human and mouse and PR signaling has been shown to play a major role in the maintenance of the stem cell population. So far, however, the differential role of the PR isoforms in the regulation of the stem cell population in the breast has not been established. We propose that the altered ratio of PR A/B might affect the stem cell population expansion and self renewal in the mammary gland.

We found that mammary glands of mice overexpressing the B isoform presented a higher percentage of cells positive for stem cell markers (CD24+/CD29+) than those derived from PR-A and WT mice. Furthermore cells derived from PR-B mammary glands had increased mammosphere forming capacity compared to both PR-A and WT. Moreover, when mammosphere cultures were carried out in the presence of 4-OH-tamoxifen 10-8M, the number of mammospheres formed from mammary glands of WT and PR-A mice was reduced compared to control cultures treated with vehicle, whereas there were no differences for cultures derived from mammary glands of PR-B mice. Additionally, upon ovariectomy (OVX), mammary glands from PR-A and WT mice showed a higher percentage of cells positive for stem cell markers by flow cytometry, and increase mammosphere forming capacity than control sham mice, while in mammary glands derived from PR-B OVX mice neither parameters changed.

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 those derived from PR-B mice.

Citation Format: Maria S. Recouvreux, Rocio Sampayo, Marina Simian. Progesterone receptor isoform ratio regulates the stem cell population in the mouse mammary gland. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2240. doi:10.1158/1538-7445.AM2015-2240