Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients.
OBJECTIVE
The Cu efflux transporter ATP7A is overexpressed in some cisplatin-resistant ovarian carcinoma cell lines. We examined the expression of ATP7A in the major normal human organs and in several types of human malignancies and sought to determine whether ATP7A expression changed during treatment of ovarian carcinomas with Pt-containing regimens.


METHODS
ATP7A expression was quantified by immunohistochemical staining using microarrays containing normal and malignant tissues, and standard sections of 54 paired tumor samples obtained from ovarian carcinoma patients before and after at least two cycles of platinum-based therapy.


RESULTS
ATP7A was expressed in normal endometrium, prostate, testis, and kidney but was not detected in the other major organs. ATP7A was expressed in some of the most common human malignancies, including prostate (7 of 7), breast (10 of 10), lung (8 of 8), colon (5 of 8), and ovary (6 of 7), as well as in a wide variety of other types of malignancy. ATP7A staining was detected in 28 of 54 ovarian carcinomas before treatment. Patients with increased ATP7A expression after treatment (18 of 54) exhibited poorer actuarial survival (P<0.0057 by log-rank test). Expression of ATP7A either before or after treatment was not associated with other clinical factors.


CONCLUSIONS
Although ATP7A is not detectable in most normal tissues it is expressed in a considerable fraction of many common tumor types. Enrichment of the tumor for ATP7A-expressing cells during platinum drug-based treatment of ovarian cancers is associated with poor survival. These findings are in agreement with results of in vitro studies from this laboratory demonstrating that increased expression of ATP7A renders cells resistant to cisplatin and carboplatin.
Samimi
Goli
G
Department of Medicine and the Cancer Center, University of California-San Diego, La Jolla, California 92093-0058, USA.
Varki
Nissi M
NM
Wilczynski
Sharon
S
Safaei
Roohangiz
R
Alberts
David S
DS
Howell
Stephen B
SB
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D027682:Cation Transport Proteins / Q000378:metabolism*; D002945:Cisplatin / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D015996:Survival Rate
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; D003300:Copper; D016190:Carboplatin; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D002945:Cisplatin