DNA Replication Licensing and Progenitor Numbers Are Increased by Progesterone in Normal Human Breast

Abstract

Proliferation in the nonpregnant human breast is highest in the luteal phase of the menstrual cycle when serum progesterone levels are high, and exposure to progesterone analogues in hormone replacement therapy is known to elevate breast cancer risk, yet the proliferative effects of progesterone in the human breast are poorly understood. In a model of normal human breast, we have shown that progesterone increased incorporation of 5-bromo-2'-deoxyuridine and increased cell numbers by activation of pathways involved in DNA replication licensing, including E2F transcription factors, chromatin licensing and DNA replication factor 1 (Cdt1), and the minichromosome maintenance proteins and by increased expression of proteins involved in kinetochore formation including Ras-related nuclear protein (Ran) and regulation of chromosome condensation 1 (RCC1). Progenitor cells competent to give rise to both myoepithelial and luminal epithelial cells were increased by progesterone, showing that progesterone influences epithelial cell lineage differentiation. Therefore, we have demonstrated that progesterone augments proliferation of normal human breast cells by both activating DNA replication licensing and kinetochore formation and increasing bipotent progenitor numbers.

CDB-4124, a Progesterone Receptor Modulator, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation and Inducing Apoptosis

“…Importantly, here the effects of progesterone agonists in T47D cells have been seen as clearly antiproliferative (35,36). The data reporting the stimulatory effects of progesterone on breast cancer development in postmenopausal women (1-3, 37, 38) and the luteal effects of progesterone in the breast (39) are 2 cases that point to progesterone as a bad player with respect to proliferation. Our own work that reported on the effects of progesterone and antiprogestins on DMBAinduced tumors (12), in conjunction with that given here, Future studies should also address questions regarding the role of CDB-4124 alone, or in combination with tamoxifen or other specific estrogen receptor modulators (SERMs) on the modulation of ER and PR signaling, and/ or on potential involvement of coactivators and corepressors.…”

The Role of Sex Steroid Receptors on Lipogenesis in Breast and Prostate Carcinogenesis: A Viewpoint

“…This could be due to their anti-estrogenic activity [45] and/or to triglycerides accumulation in lipid droplets observed in T47 D cells [46]. However, in normal human mammary glands growing within a Matrigel matrix [47], progesterone appears to be mitogenic, and lipid droplets generally do not accumulate in vivo in breast or prostate cancer [36]. Actually, epidemiological studies strongly suggest that progestins stimulate breast carcinogenesis.…”

“…These proteins may not be as necessary in vitro than they are in vivo. It has also been proposed that progestins might reactivate cancer stem cells [51] or stimulate progenitor cells in normal breast [47]. Finally, the effect of progestins may be different on normal or transformed mammary glands.…”

Introduction: Hormonal Regulation of Mammary Development and Milk Protein Gene Expression at the Whole Animal and Molecular Levels

“…This article and the many that followed [15,16] ushered in the molecular era in our understanding of the regulation of milk secretion. For an entrée into the current literature on this subject the reader is referred to several timely reviews in this journal [17][18][19][20][21][22][23] as well as key current articles [24][25][26][27].…”