Expression profiling of human breast cancers and gene regulation by progesterone receptors

被引:42
作者
Jacobsen, BM [1 ]
Richer, JK [1 ]
Sartorius, CA [1 ]
Horwitz, KB [1 ]
机构
[1] Univ Colorado, Sch Med, Dept Med, Div Endocrinol, Denver, CO 80262 USA
关键词
human breast cancer; gene arrays; progesterone receptors; PR isoforms; ligand-independent regulation;
D O I
10.1023/B:JOMG.0000010028.48159.84
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Even the first expression profiling studies of breast cancers have generated new insights. They suggest for example, that information about tumor aggressiveness, prognosis, metastatic potential, or treatment outcome is encoded in, and can be deduced from, the primary tumor. On the other hand no clinical genomic array data have yet been published that deal with hormonal aspects of breast tumorigenesis, tumor progression, or therapeutics. Rather, studies have focused on experimental model systems. We review below the currently published data on array profiling in clinical breast cancer, then describe our studies in breast cancer cell lines and xenograft models dealing with progesterone receptors ( PRs) and the role of progesterone. We demonstrate that the two PR isoforms, PR-A and PR-B, have mostly nonoverlapping molecular signatures when liganded by progesterone, with PR-B the more active form. Additionally, we document the surprising finding that unliganded PRs can regulate gene transcription, with PR-A the more active form. In ovariectomized mice supplemented with estradiol but lacking measurable progesterone, PR-B-expressing tumors grow to twice the size of PR-A-expressing ones. We conclude that in breast cancers, PRs are more than simple markers of estrogen receptor function. Rather, presence of PRs and the ratio of the two isoforms directly influence tumor phenotype, even in the absence of ligand.
引用
收藏
页码:257 / 268
页数:12
相关论文
共 91 条
[61]   Multiclass cancer diagnosis using tumor gene expression signatures [J].
Ramaswamy, S ;
Tamayo, P ;
Rifkin, R ;
Mukherjee, S ;
Yeang, CH ;
Angelo, M ;
Ladd, C ;
Reich, M ;
Latulippe, E ;
Mesirov, JP ;
Poggio, T ;
Gerald, W ;
Loda, M ;
Lander, ES ;
Golub, TR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (26) :15149-15154
[62]   DNA microarrays in clinical oncology [J].
Ramaswamy, S ;
Golub, TR .
JOURNAL OF CLINICAL ONCOLOGY, 2002, 20 (07) :1932-1941
[63]   Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells [J].
Richer, JK ;
Jacobsen, BM ;
Manning, NG ;
Abel, MG ;
Wolf, DM ;
Horwitz, KB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (07) :5209-5218
[64]   The C/EBPβ transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland [J].
Robinson, GW ;
Johnson, PF ;
Hennighausen, L ;
Sterneck, E .
GENES & DEVELOPMENT, 1998, 12 (12) :1907-1916
[65]   Systematic variation in gene expression patterns in human cancer cell lines [J].
Ross, DT ;
Scherf, U ;
Eisen, MB ;
Perou, CM ;
Rees, C ;
Spellman, P ;
Iyer, V ;
Jeffrey, SS ;
Van de Rijn, M ;
Waltham, M ;
Pergamenschikov, A ;
Lee, JCE ;
Lashkari, D ;
Shalon, D ;
Myers, TG ;
Weinstein, JN ;
Botstein, D ;
Brown, PO .
NATURE GENETICS, 2000, 24 (03) :227-235
[66]   A 3RD TRANSACTIVATION FUNCTION (AF3) OF HUMAN PROGESTERONE RECEPTORS LOCATED IN THE UNIQUE N-TERMINAL SEGMENT OF THE B-ISOFORM [J].
SARTORIUS, CA ;
MELVILLE, MY ;
HOVLAND, AR ;
TUNG, L ;
TAKIMOTO, GS ;
HORWITZ, KB .
MOLECULAR ENDOCRINOLOGY, 1994, 8 (10) :1347-1360
[67]  
SARTORIUS CA, 1993, J BIOL CHEM, V268, P9262
[68]  
SARTORIUS CA, IN PRESS BREAST CANC
[69]   Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk [J].
Schairer, C ;
Lubin, J ;
Troisi, R ;
Sturgeon, S ;
Brinton, L ;
Hoover, R .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2000, 283 (04) :485-491
[70]   QUANTITATIVE MONITORING OF GENE-EXPRESSION PATTERNS WITH A COMPLEMENTARY-DNA MICROARRAY [J].
SCHENA, M ;
SHALON, D ;
DAVIS, RW ;
BROWN, PO .
SCIENCE, 1995, 270 (5235) :467-470