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

Westmead Institute for Cancer Research (J.D.G., P.A.M., U.S., R.L.B., C.L.C.), Westmead Millennium Institute, Westmead Hospital, Translational Oncology (R.L.B., C.L.C.), Sydney West Area Health Service, and Children’s Medical Research Institute (L.I.H., R.R.R.), Westmead, New South Wales 2145, Australia; Faculty of Medical Sciences (J.H.v.D.), University of Groningen, 9700 AB Groningen, The Netherlands; and University of Sydney (J.D.G., P.A.M., U.S., R.L.B., L.I.H., R.R.R., C.L.C.), New South Wales 2006, Australia

Address all correspondence and requests for reprints to: Dr. Christine L. Clarke, Westmead Institute for Cancer Research, Westmead Hospital, Westmead, New South Wales 2145, Australia. E-mail: christine_clarke{at}wmi.usyd.edu.au.

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.

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