CONICET | Buscador de Institutos y Recursos Humanos

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 previously showed that cells derived from mammary glands of PRB mice present a higher percentage of stem cells (p=0.003), and increased mammosphere-forming capacity (p=0.0016) than those derived from WT and PRA. Also, we described that upon ovariectomy (OVX), there is an increment in stem cells and mammosphere forming capacity only in WT and PRA mice. Surprisingly, we found that the morphology of mammospheres derived from WT, PRA and PRB were morfologically different. PRA mammospheres are mostly solid, while PRB are mostly hollow, and WT show both types. Upon OVX, WT and PRA mammospheres become hollow, while there are no changes in PRB. To further study ovarian hormones regulation, we performed in vitro treatments with antiestrogens (ICI 182,780), E or vehicle and found that ICI led to an increase in mammosphere forming capacity (p