title: Disease Subtype-Independent Biomarkers of Breast Cancer Chemoprevention by the Ayurvedic Medicine Phytochemical Withaferin A.
abstract: A nontoxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study was undertaken to determine the efficacy of an Ayurvedic medicine phytochemical (Withaferin A, [WA]) for chemoprevention of breast cancer and to elucidate its mode of action.
  
  
  
  Chemopreventive efficacy of WA (4 and 8 mg/kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU; n = 14 for control group, n = 15 for 4 mg/kg group, and n = 18 for 8 mg/kg group). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by immunoblotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat (n = 8-12 for control group, n = 7-11 for 4 mg/kg group, and n = 8-12 for 8 mg/kg group) and/or mouse mammary tumor virus-neu (MMTV-neu) models (n = 4-11 for control group and n = 4-21 for 4 mg/kg group). Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and/or MDA-MB-231 cells. All statistical tests were two-sided.
  
  
  
  Incidence, multiplicity, and burden of breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8 mg/kg group was lower by about 68% compared with controls (8 mg/kg vs control, mean = 2.76 vs 8.59, difference = -5.83, 95% confidence interval of difference = -9.89 to -1.76, P = .004). Mitotic arrest and apoptosis induction were some common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured breast cancer cells.
  
  
  
  WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.
authors.affiliation: Department of Pharmacology and Chemical Biology.
authors.forename: Suman K
authors.initials: SK
authors.lastname: Samanta
authors.affiliation: Department of Pharmacology and Chemical Biology.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Sehrawat
authors.affiliation: Department of Pharmacology and Chemical Biology.
authors.forename: Su-Hyeong
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Chemical Biology.
authors.forename: Eun-Ryeong
authors.initials: ER
authors.lastname: Hahm
authors.affiliation: Department of Biostatistics.|University of Pittsburgh Cancer Institute.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Shuai
authors.affiliation: Department of Pharmacology and Chemical Biology.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Roy
authors.affiliation: Department of Pharmacology and Chemical Biology.
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Pore
authors.affiliation: Department of Pharmacology and Chemical Biology.
authors.forename: Krishna B
authors.initials: KB
authors.lastname: Singh
authors.affiliation: University of Pittsburgh Cancer Institute.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Christner
authors.affiliation: University of Pittsburgh Cancer Institute.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Department of Pharmacology and Chemical Biology.|University of Pittsburgh Cancer Institute.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Department of Pharmacology and Chemical Biology.|University of Pittsburgh Cancer Institute.
authors.forename: Shivendra V
authors.initials: SV
authors.lastname: Singh
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000105:Acetyl Coenzyme A / Q000097:blood; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000139:chemically induced / Q000737:chemistry / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D014450:Electron Transport Complex III / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D019344:Lactic Acid / Q000097:blood; D020738:Leptin / Q000097:blood; D061986:MCF-7 Cells; D008293:Malates / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000737:chemistry / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse; D008770:Methylnitrosourea; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D008940:Mitotic Index; D051381:Rats; D011960:Receptors, Estrogen / Q000032:analysis; D050697:Retinal Dehydrogenase / Q000032:analysis; D012192:Retroviridae Infections / Q000150:complications*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden; D014412:Tumor Virus Infections / Q000150:complications*; D054358:Withanolides / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D051858:Forkhead Transcription Factors; C484580:FoxQ1 protein, rat; D019394:Ki-67 Antigen; D020738:Leptin; D008293:Malates; D011960:Receptors, Estrogen; D054358:Withanolides; D019344:Lactic Acid; D008770:Methylnitrosourea; D000105:Acetyl Coenzyme A; C030298:malic acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000080924:Aldehyde Dehydrogenase 1 Family; C523119:Aldh1a1 protein, rat; D050697:Retinal Dehydrogenase; D014450:Electron Transport Complex III; D003849:Deoxyguanosine; C009684:withaferin A