title: Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy.
abstract: BACKGROUND
  Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment.
  
  
  METHODS
  In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601).
  
  
  RESULTS
  Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14% and 52% of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25% vs 67% for clinical response, p = 0.011, N = 51; 0% vs 41% for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not.
  
  
  CONCLUSIONS
  Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE.
  
  
  BACKGROUND
  UMIN C000000345 (2006/03/06).
authors.affiliation: Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan. t-ueno@ks.kyorin-u.ac.jp.|Department of Breast Surgery, Kyorin University Hospital, 6-20-2 Shinkawa Mitaka, 181-8611, Tokyo, Japan. t-ueno@ks.kyorin-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Target Therapy Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shigehira
authors.initials: S
authors.lastname: Saji
authors.affiliation: Institute for Advanced Biosciences Keio University, Yamagata, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Masuda
authors.affiliation: Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Kuroi
authors.affiliation: Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Division of Breast Surgery, Saitama Cancer Center, Saitama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takei
authors.affiliation: Department of Breast and Endocrine Surgery, Kumamoto University, Kumamoto, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Breast and Endocrine Surgery, Hokkaido University Hospital, Sapporo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Hiroshima City Asa Hospital, Hiroshima, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Hisamatsu
authors.affiliation: National Hospital Organization Shikoku Cancer Center, Ehime, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Aogi
authors.affiliation: Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Department of Breast Surgery, Kyorin University Hospital, 6-20-2 Shinkawa Mitaka, 181-8611, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Imoto
authors.affiliation: Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.affiliation: Department of Breast Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
mesh_terms: D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071186:Beclin-1 / Q000096:biosynthesis* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis
chemical_list: D000730:Androstadienes; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C056516:exemestane
keywords: Aromatase inhibitor; Autophagy; Beclin 1; Breast cancer; Ki-67; Neoadjuvant endocrine therapy