The mammary gland is a complex organ whose growth and development are controlled by the interaction of a wide variety of hormones and growth factors also involved in the etiology and progression of the cancerous state. Our emphasis has been on the interactions of prolactin (PRL), estrogens (E), and progesterone (P), with recent work also examining how epidermal growth factor (EGF), and transforming growth factors alpha and beta are affected by the interplay of these three classical hormones. Lobulo-alveolar development of the mammary gland requires the priming action of both E and P to induce EGF receptors and production of EGF-like growth factors. E induces the P receptor at branch points of the ductal tree; P induces the Hox-related gene Msx-2 and DNA synthesis thus promotes branching morphogenesis. In concert with insulin, PRL and glucocorticoids, EGF or TGF-alpha can promote full lobulo-alveolar development in vitro. Programmed cell death occurs within 3 days of removal of PRL. PRl acts as a mitogen in vitro to induce growth of human breast cancer cells. This induced growth can be blocked by non-steroidal antiestrogens such as tamoxifen (TAM) and the steroidal pure antiestrogens ICI182780 and ICI164384. This action occurs directly through the PRL receptor and results in an increase in programmed cell death. Neonatal exposure to TAM results in an adult mouse with poorly developed mammary glands containing more pre- neoplastic hyperplastic alveolar nodules. Serum PRL levels in the treated animals are constitutively elevated. The importance of PRL in human breast disease was confirmed by studies in MCF-7 and T47Dco cells which show that biologically active PRL is synthesized and secreted by these human breast cancer cells. Growth of both ER- and ER+ human breast cancer cells is inhibited by 70-85% by anti-PRL antibodies and by antisense RNA for PRL. Conditioned media and extracts from cells precipitated with anti-PRL antibodies, contain a single band of approximately 22kDa, the size of pituitary PRL. The coding region for the PRL gene from mammary cells is at least 96% identical to that from the pituitary. By RT-PCR, >80% of human breast cancer cell lines and breast cancer biopsies have PRL mRNA. Cancerous tissue has significantly more PRL and PRL receptor mRNA than adjacent, non- involved tissue from the same patient. Only 30% of normal tissue expressed mRNA for the short form of the PRL receptor while 78% of the cancerous tissue expressed mRNA for this form. The most significant regulator of PRL synthesis by the mammary gland is PRL itself. High levels of exogenous PRL in the culture medium inhibits the level of PRL RNA in T47D cells by more than 80%. Treating nulliparous mice with the PRL secretion inhibiting drug bromocriptine resulted in a 30 fold increase in the level of mRNA for PRL in the mammary glands. These data suggest an autocrine role of PRL in human breast cancer which is regulated by a feed-back mechanism. These observations may have implications in therapy. - breast cancer, Cancer cell growth regulation, cell proliferation, Hormones, mammary gland, receptor signaling, receptors, prolactin, - Human Tissues, Fluids, Cells, etc. & Neither Human Subjects nor Human Tissues

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008226-24
Application #
6433086
Study Section
(LTIB)
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Li, W; Xiao, C; Vonderhaar, B K et al. (2007) A role of estrogen/ERalpha signaling in BRCA1-associated tissue-specific tumor formation. Oncogene 26:7204-12
Satoh, K; Hovey, R C; Malewski, T et al. (2007) Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2. Oncogene 26:7526-34
Faupel-Badger, Jessica M; Prindiville, Sheila A; Venzon, David et al. (2006) Effects of raloxifene on circulating prolactin and estradiol levels in premenopausal women at high risk for developing breast cancer. Cancer Epidemiol Biomarkers Prev 15:1153-8
Koduri, Sailaja; Goldhar, Anita S; Vonderhaar, Barbara K (2006) Activation of vascular endothelial growth factor (VEGF) by the ER-alpha variant, ERDelta3. Breast Cancer Res Treat 95:37-43
Hovey, Russell C; Asai-Sato, Mikiko; Warri, Anni et al. (2005) Effects of neonatal exposure to diethylstilbestrol, tamoxifen, and toremifene on the BALB/c mouse mammary gland. Biol Reprod 72:423-35
Tan, Dunyong; Johnson, David A; Wu, Wei et al. (2005) Unmodified prolactin (PRL) and S179D PRL-initiated bioluminescence resonance energy transfer between homo- and hetero-pairs of long and short human PRL receptors in living human cells. Mol Endocrinol 19:1291-303
Goldhar, Anita S; Vonderhaar, Barbara K; Trott, Josephine F et al. (2005) Prolactin-induced expression of vascular endothelial growth factor via Egr-1. Mol Cell Endocrinol 232:9-19
Bianco, Caterina; Strizzi, Luigi; Ebert, Andreas et al. (2005) Role of human cripto-1 in tumor angiogenesis. J Natl Cancer Inst 97:132-41
Asai-Sato, Mikiko; Nagashima, Yoji; Miyagi, Etsuko et al. (2005) Prolactin inhibits apoptosis of ovarian carcinoma cells induced by serum starvation or cisplatin treatment. Int J Cancer 115:539-44
Wu, Wei; Ginsburg, Erika; Vonderhaar, Barbara K et al. (2005) S179D prolactin increases vitamin D receptor and p21 through up-regulation of short 1b prolactin receptor in human prostate cancer cells. Cancer Res 65:7509-15

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