The biology of progesterone receptor in the normal mammary gland and in breast cancer

Abstract

This paper reviews work on progesterone and the progesterone receptor (PR) in the mouse mammary gland that has been used extensively as an experimental model. Studies have led to the concept that progesterone controls proliferation and morphogenesis of the luminal epithelium in a tightly orchestrated manner at distinct stages of development by paracrine signaling pathways, including receptor of activated nuclear factor κ ligand (RANKL) as a major paracrine factor. Progesterone also drives expansion of stem cells by paracrine signals to generate progenitors required for alveologenesis. During mid-to-late pregnancy, progesterone has another role to suppress secretory activation until parturition mediated in part by crosstalk between PR and prolactin/Stat5 signaling to inhibit induction of milk protein gene expression, and by inhibiting tight junction closure. In models of hormone-dependent mouse mammary tumors, the progesterone/PR signaling axis enhances pre-neoplastic progression by a switch from a paracrine to an autocrine mode of proliferation and dysregulation of the RANKL signaling pathway. Limited experiments with normal human breast show that progesterone/PR signaling also stimulates epithelial cell proliferation by a paracrine mechanism; however, the signaling pathways and whether RANKL is a major mediator remains unknown. Work with human breast cancer cell lines, patient tumor samples and clinical studies indicates that progesterone is a risk factor for breast cancer and that alteration in progesterone/PR signaling pathways contributes to early stage human breast cancer progression. However, loss of PR expression in primary tumors is associated with a less differentiated more invasive phenotype and worse prognosis, suggesting that PR may limit later stages of tumor progression.

Original Research: Featured Article: Imatinib mesylate (Gleevec) inhibits Notch and c-Myc signaling: Five-day treatment permanently rescues mammary development

“…In the young adult mouse mammary gland, progesterone regulates side branching, while in pregnancy, the steroid hormones estrogen and progesterone, in addition to prolactin all play roles in alveolar expansion. 66 Interestingly, Notch signaling directly or indirectly interacts with or cross talks with estrogen, 67 progesterone, progesterone receptor, 68 Gata3, 69,70 prolactin, and the Elf5 transcription factor. 71 Previously, we found that c-Kit expression is up-regulated in Wap-Int3 mammary tumors.…”

Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer

“…Cyclin D1 is required for the proliferation of ER+/PgR+ cells, and in line with this cyclin D1 is commonly amplified and overexpressed in ER/PgR+ breast tumours [32]. Paracrine signalling may be more important in ER-/PgR-breast cancer, and progesterone has been shown to stimulate proliferation of ER-/PgR-cells only in the presence of RANKL [31] Features of tumourigenesis: the hallmarks of cancer…”

“…PgR, encoded by the PR gene at 11q13 exists in two isoforms, PgRA and PgRB, where PgRA has a shorter amino terminal domain [31]. In vitro, PgRB is a stronger transcriptional activator than PgRA.…”

“…In general, sustained high levels of oestrogen and progesterone are predisposing for breast cancer, but as clinical markers ER and PgR are associated with low grade tumours, a favourable short-term prognosis and response to endocrine therapies [32]. Alterations in the balance between PgRA and PgRB have been observed in tumour cells, and a high PgRA/PgRB has been associated with poor prognosis and less response to endocrine therapies [31]. In the majority of neoplasms, the population of proliferating ER+/PgR+ luminal epithelial cells is increasing, likely as a result of a switch from paracrine to autocrine steroid hormone signalling through RANKL.…”

Fibrocystic disease and breast cancer risk (а review of literature)

“…Высокий уровень эстрогенов стимулирует клеточный рост и пролиферацию млечных протоков на протяжении каждого менструального цикла [66]. Прогестерон стимулирует 17-бета-гидроксистероид-дегидрогеназу 2-го типа, преобразующую эстрадиол в менее активный эстрон [67].…”