title: Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptors status or adjuvant endocrine therapy.
abstract: BACKGROUND
  Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2. In breast cancer, however, Bcl-2 expression has been reported to be a favorable prognostic factor. The positive correlation of Bcl-2 with estrogen receptor (ER)/progesterone receptor (PR) status, and endocrine therapy frequently given for hormone receptor-positive tumors, may obscure the independent pathobiological role of Bcl-2. We constructed a large systematic study to determine whether Bcl-2 has an independent role in breast cancer.
  
  
  METHODS
  Bcl-2 expression was immunohistochemically evaluated and compared with other clinicopathological factors, including clinical outcome, in 1081 breast cancer cases with long follow-up, separately analyzing 634 cases without any adjuvant therapy and 447 cases with tamoxifen monotherapy. The χ (2)-test for independence using a contingency table, the Kaplan-Meier method with the log-rank test, and a Cox proportional hazards model were used for the comparison of clinicopathological factors, assessment of clinical outcome, and multivariate analyses, respectively.
  
  
  RESULTS
  In both patient groups, Bcl-2 expression strongly correlated with positive ER/PR status, low grade, negative human epidermal growth factor receptor 2 (HER2) status, and small tumor size, as previously reported. Bcl-2 expression did not independently predict clinical outcome in patients with ER-positive and/or PR-positive tumors or in those who received tamoxifen treatment; however, it was an independent unfavorable prognostic factor in patients with ER-negative/PR-negative or triple-negative (ER-negative/PR-negative/HER2-negative) tumors who received no adjuvant therapy. The latter was even more evident in postmenopausal women: those with hormone receptor-negative or triple-negative tumors lacking Bcl-2 expression showed a favorable outcome.
  
  
  CONCLUSIONS
  Bcl-2 expression is an independent poor prognostic factor in patients with hormone receptor-negative or triple-negative breast cancers, especially in the absence of adjuvant therapy, suggesting that the anti-apoptotic effect of Bcl-2 is clearly exhibited under such conditions. The prognostic value of Bcl-2 was more evident in postmenopausal women. The present findings also highlight Bcl-2 as a potential therapeutic target in breast cancers lacking conventional therapeutic targets such as triple-negative tumors. The favorable prognosis previously associated with Bcl-2-positive breast cancer probably reflects the indirect effect of frequently coexpressed hormone receptors and adjuvant endocrine therapy.
authors.affiliation: Department of Pathology, School of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan. naoko.honma@med.toho-u.ac.jp.|Department of Pathology, Cancer Institute, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. naoko.honma@med.toho-u.ac.jp.
authors.forename: Naoko
authors.initials: N
authors.lastname: Honma
authors.affiliation: Department of Pathology, Cancer Institute, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. rhorii-pathology@jfcr.or.jp.
authors.forename: Rie
authors.initials: R
authors.lastname: Horii
authors.affiliation: Breast Medical Oncology, Breast Oncology Center, Cancer Institute Hospital, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. yito@jfcr.or.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Medical Oncology, Fukushima Medical University, School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima, 960-1295, Japan. ss-saji@wa2.so-net.ne.jp.
authors.forename: Shigehira
authors.initials: S
authors.lastname: Saji
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Medical School, 6431 Fannin, MSB 2.270, Houston, TX, 77030, USA. mamoun.younes@uth.tmc.edu.
authors.forename: Mamoun
authors.initials: M
authors.lastname: Younes
authors.affiliation: Breast Oncology Center, Cancer Institute Hospital, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. takuji.iwase@jfcr.or.jp.
authors.forename: Takuji
authors.initials: T
authors.lastname: Iwase
authors.affiliation: Department of Pathology, Cancer Institute, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. fakiyama@jfcr.or.jp.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Akiyama
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D013629:Tamoxifen / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen