Pilot study of rosiglitazone therapy in women with breast cancer: effects of short-term therapy on tumor tissue and serum markers.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a steroid nuclear receptor that is activated by natural compounds such as specific fatty acids and synthetic drugs such as thiazolidinedione antidiabetic agents. Expressed in normal and malignant mammary epithelial cells, activation of PPARgamma is associated with antiproliferative effects on human breast cancer cells in preclinical studies. The purpose of this study was to test the hypothesis that PPARgamma ligand therapy might inhibit tumor growth and progression in human breast cancer.


METHODS
We conducted a pilot trial of short-term (2-6 weeks) treatment with the thiazolidinedione rosiglitazone in 38 women with early-stage (T(is)-T(2), N(0-1), M(0)) breast cancer, administered between the time of diagnostic biopsy and definitive surgery.


RESULTS
Short-term treatment with rosiglitazone (8 mg/d) did not elicit significant effects on breast tumor cell proliferation using Ki67 expression as a measure of cell proliferation and surrogate marker of tumor growth and progression. In pretreatment tumors notable for nuclear expression of PPARgamma by immunohistochemistry, down-regulation of nuclear PPARgamma expression occurred following rosiglitazone administration (P = 0.005). No PPARG mutations were identified, and the incidence of P12A and H446H polymorphisms did not differ relative to U.S. controls (P = 0.5). Treatment with rosiglitazone resulted in increased serum adiponectin (P < 0.001), decreased insulin levels (P = 0.005), and increased insulin sensitivity (P = 0.004). Rosiglitazone was well tolerated without serious adverse events.


CONCLUSIONS
Our data indicate that short-term rosiglitazone therapy in early-stage breast cancer patients leads to local and systemic effects on PPARgamma signaling that may be relevant to breast cancer.
Yee
Lisa D
LD
Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio, USA. lisa.yee@osumc.edu
Williams
Nita
N
Wen
Ping
P
Young
Donn C
DC
Lester
Joanne
J
Johnson
Maria V
MV
Farrar
William B
WB
Walker
Michael J
MJ
Povoski
Stephen P
SP
Suster
Saul
S
Eng
Charis
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D047495:PPAR gamma / Q000378:metabolism; D010865:Pilot Projects; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D019394:Ki-67 Antigen; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone