Low expression of galectin-3 is associated with poor survival in node-positive breast cancers and mesenchymal phenotype in breast cancer stem cells.
Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness.



To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression.



Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3negativeBCSCs were associated with enhanced tumorigenicity in orthotopic mouse models.



Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.
Current address: Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich (LMU), Munich, Germany.
Matthias
0000-0001-9597-1368
M
Ilmer
Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Nachman
N
Mazurek
Department of Pathology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Michael Z
MZ
Gilcrease
Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
James C
JC
Byrd
Department of Breast Radiation Oncology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Wendy A
WA
Woodward
Department of Breast Radiation Oncology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Thomas A
TA
Buchholz
Department of Stem Cell Transplantation and Cellular Therapies, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Kim
K
Acklin
Department of Stem Cell Transplantation and Cellular Therapies, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Karen
K
Ramirez
Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Margarete
M
Hafley
Department of Medicine, Tulane University Health Science Center, New Orleans, LA, USA.
Eckhard
E
Alt
Department of Translational Molecular Pathology, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA.
Jody
J
Vykoukal
Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center (MDACC), University of Texas Health Science Center at Houston, Houston, TX, USA. rbresali@mdanderson.org.
Robert S
RS
Bresalier
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D037502:Galectin 3 / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway; D055815:Young Adult
D014408:Biomarkers, Tumor; D037502:Galectin 3; D051057:Proto-Oncogene Proteins c-akt
Breast cancer; Cancer stem cells (CSC); Epithelial-mesenchymal transition (EMT); Galectin-3 (Gal3)
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