Influence of the C5a-C5a receptor system on breast cancer progression and patient prognosis.
BACKGROUND
Emerging evidence has shown activation of the complement system in cancer tissues and anaphylatoxin C5a release from C5 by cancer cells, suggesting C5a as a component in the cancer microenvironment. We revealed aberrant expression of C5a receptor (C5aR) in various human cancers and C5a-elicited enhancement of C5aR-expressing cancer cell invasion.


METHODS
To explore an influence of the C5a-C5aR system in breast cancer (BC), we investigated BC C5aR expression in relation to clinicopathological parameters of the patients and an effect of C5a on BC cell proliferation.


RESULTS
BC cell C5aR expression was observed immunohistochemically in 22 of 171 patients (13 %) and related to larger tumor size, higher nuclear grade and Ki-67 labeling index, presence of lymph node metastasis and advanced clinical stages. Interestingly, BC cells were C5aR-negative in all patients with BC in situ and C5aR-positive rate was high (38 %) in patients with hormone receptor-negative, namely triple-negative BC. For BC cells in metastasized lymph nodes, 12 of 22 patients (55 %) were C5aR-positive and included 7 patients with C5aR-negative BC in the primary site. Survival rate of patients with C5aR-positive BC was lower than that of patients with C5aR-negative BC. C5a enhanced proliferation of C5aR-expressing triple-negative BC cells in a C5aR-dependent manner.


CONCLUSIONS
Relation of BC C5aR expression to tumor development and poor prognosis of the patients and proliferation enhancing effect of C5a on C5aR-expressing BC cells suggest that the C5a-C5aR system is closely associated with BC progression. This system may be a new target to treat BC patients, particularly with triple-negative BC.
Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. taka@kumamoto-u.ac.jp.
Takahisa
T
Imamura
Department of Breast and Endocrine Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Mutsuko
M
Yamamoto-Ibusuki
Department of Breast and Endocrine Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Aiko
A
Sueta
Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
Tatsuko
T
Kubo
Department of Immunogenetics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Atsushi
A
Irie
Medical Quality Management Center, Kumamoto University Hospital, Kumamoto, Japan.
Ken
K
Kikuchi
Shokei University, Kumamoto, Japan.
Toru
T
Kariu
Department of Breast and Endocrine Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Hirotaka
H
Iwase
D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy
D014408:Biomarkers, Tumor; C488033:C5AR1 protein, human; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a
C5a; C5a receptor; Lymph node metastasis; Prognosis; Proliferation