The nuclear transcription factor kappaB/bcl-2 pathway correlates with pathologic complete response to doxorubicin-based neoadjuvant chemotherapy in human breast cancer.
OBJECTIVE
Molecular factors involved in apoptosis may affect breast cancer response to chemotherapy. Herein, we studied the nuclear factor kappaB (NF-kappaB)/bcl-2 pathway to determine whether or not activation of this antiapoptotic pathway was associated with a poor response of human breast cancer to anthracycline-based neoadjuvant chemotherapy.


METHODS
We studied 82 human breast cancer samples from patients treated with neoadjuvant doxorubicin-based chemotherapy and studied whether or not nuclear location of the transcription factor NF-kappaB was associated with expression of bcl-2 and bax and whether or not expression of these proteins correlated with chemotherapy response. Protein expression was measured with immunohistochemical staining. A dedicated breast cancer pathologist who was unaware of the clinical outcome data dichotomized the slides as positive or negative based on the presence or absence of cytoplasmic staining for bcl-2 and bax or nuclear staining for NF-kappaB.


RESULTS
Sixty-one percent of the tumors were positive for bcl-2, 85% were positive for bax, and 16% were positive for NF-kappaB. All bcl-2-positive tumors were also bax positive (P < 0.0001) and all NF-kappaB-positive tumors were both bcl-2 positive (P = 0.001) and bax positive (P = 0.113). Eleven of the 82 patients (13%) had a pathologic complete response (pCR) to chemotherapy. Patients with positive staining tumors for any of the markers less commonly achieved a pCR to chemotherapy than those with negative tumor staining. The pCR rates were NF-kappaB positive 0% (0 of 13) versus NF-kappaB negative 13% (11 of 69; P = 0.130); bcl-2 positive 4% (2 of 49) versus bcl-2 negative 27% (9 of 33; P = 0.004); and bax positive 6% (4 of 69) versus bax negative 58% (7 of 12; P < 0.001).


CONCLUSIONS
We conclude that nuclear localization of NF-kappaB correlates with bcl-2 and bax expression and that the NF-kappaB/bcl-2 pathway may be associated with a poor response to neoadjuvant doxorubicin-based chemotherapy.
Buchholz
Thomas A
TA
Department of Radiation Oncology, Breast Medical Oncology, Surgical Oncology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. tbuchhol@mdanderson.org
Garg
Amit K
AK
Chakravarti
Nitin
N
Aggarwal
Bharat B
BB
Esteva
Francisco J
FJ
Kuerer
Henry M
HM
Singletary
S Eva
SE
Hortobagyi
Gabriel N
GN
Pusztai
Lajos
L
Cristofanilli
Massimo
M
Sahin
Aysegul A
AA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D002467:Cell Nucleus / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000627:therapeutic use; D003593:Cytoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil