Resistance to Tamoxifen: A Consequence of Altered P27Kipl Regulation During Breast Cancer PDF Download

Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0

Get Book Here

Book Description
While approximately 70% of breast cancers express the estrogen receptor (ER) at diagnosis, only two thirds of these will respond to antiestrogens such as Tamoxifen (TAM). Unfortunately, ER positive tumors that are initially responsive, invariably acquire resistance to hormonal therapies (reviewed in (1)).: TAM-resistant tumors usually show continued expression of the ER (2, 3). Estradiol regulates cell proliferation and development in the mammary gland. The elucidation of mechanisms whereby estradiol:ER influences cell cycle regulators and how these are blocked by Tamoxifen is highly relevant to the development of new treatments for steroid resistant breast cancer. Both estrogens and antiestrogens influence the cell cycle during the early Ol phase (4). The cell cycle is governed by a family of cyclin dependent kinases (cdks), whose activity is regulated by positive effectors, the cyclins, by phosphorylation and by negative regulators, the cdk inhibitors (reviewed in (5-7)). p27 or kinase inhibitor protein 1 (KIP 1) is strongly expressed in normal mammary epfthelial cells (8). That p27 protein levels are frequently reduced in primary breast cancers and this correlates with poor prognosis, suggests that p27 is an important negative regulator of the normal breast cell cycle (8-10) . The cellular abundance of p27 is importantly regulated by ubiquitin-mediated proteolysis (11). p27 protein decreases when quiescent MCF-7 breast cancer cells are stimulated to reenter the cell cycle with estradiol treatment and p27 increases when antiestrogens induce Gi arrest ((12, 13) and PNAS manuscript appended).