Anti-estrogenic mechanism of unliganded progesterone receptor isoform B in breast cancer cells.
Over half of breast cancer cases are estrogen-dependent and strategies to combat estrogen-dependent breast cancer have been to either block the activation of estrogen receptor (ER) or diminish the supply of estrogens. Our previous work documented that estrogen-independent expression of progesterone receptor (PR) in MCF-7 cells markedly disrupted the effects of estrogen. In this study, we have developed an adenovirus-mediated gene delivery system to study the specific involvement of PR isoform A (PR-A) and PR-B in the anti-estrogenic effect and its mechanism of action. The results revealed that PR-B, but not PR-A, exhibited distinct anti-estrogenic effect on E2-induced cell growth, gene expression, and ER-ERE interaction in a ligand-independent manner. The anti-estrogenic effect of PR-B was also associated with heightened metabolism and increased cellular uptake of estradiol-17 beta (E2). We have also found that the B-upstream segment of PR-B alone was able to inhibit E2-induced ER-ERE interaction and cellular uptake of E2. Although PR-A alone did not affect E2-induced ER activity, it antagonized the anti-estrogenic effect of PR-B in a concentration-dependent manner. The findings suggest an important mechanism of maintaining a favorable level of ER activity by PR-A and PR-B in estrogen target cells for optimal growth and differentiation. The potential anti-estrogenic mechanism of PR-B may be exploited for breast cancer therapy.
Zheng
Ze-Yi
ZY
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Zheng
Si-Min
SM
Bay
Boon-Huat
BH
Aw
Swee-Eng
SE
C-L Lin
Valerie
V
D000256:Adenoviridae / Q000235:genetics; D020816:Amino Acid Motifs; D001943:Breast Neoplasms / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020218:Response Elements
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D004958:Estradiol