CD151 accelerates breast cancer by regulating alpha 6 integrin function, signaling, and molecular organization.
CD151, a master regulator of laminin-binding integrins (alpha(6)beta(4), alpha(6)beta(1), and alpha(3)beta(1)), assembles these integrins into complexes called tetraspanin-enriched microdomains. CD151 protein expression is elevated in 31% of human breast cancers and is even more elevated in high-grade (40%) and estrogen receptor-negative (45%) subtypes. The latter includes triple-negative (estrogen receptor, progesterone receptor, and HER2 negative) basal-like tumors. CD151 ablation markedly reduced basal-like mammary cell migration, invasion, spreading, and signaling (through FAK, Rac1, and lck) while disrupting epidermal growth factor receptor (EGFR)-alpha(6) integrin collaboration. Underlying these defects, CD151 ablation redistributed alpha(6)beta(4) integrins subcellularly and severed molecular links between integrins and tetraspanin-enriched microdomains. In a prototypical basal-like mammary tumor line, CD151 ablation notably delayed tumor progression in ectopic and orthotopic xenograft models. These results (a) establish that CD151-alpha(6) integrin complexes play a functional role in basal-like mammary tumor progression; (b) emphasize that alpha(6) integrins function via CD151 linkage in the context of tetraspanin-enriched microdomains; and (c) point to potential relevance of CD151 as a high-priority therapeutic target, with relative selectivity (compared with laminin-binding integrins) for pathologic rather than normal physiology.
Yang
Xiuwei H
XH
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Richardson
Andrea L
AL
Torres-Arzayus
Maria I
MI
Zhou
Pengcheng
P
Sharma
Chandan
C
Kazarov
Alexander R
AR
Andzelm
Milena M
MM
Strominger
Jack L
JL
Brown
Myles
M
Hemler
Martin E
ME
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039503:Integrin alpha6 / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics; D060185:Tetraspanin 24; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C554715:CD151 protein, human; C554716:Cd151 protein, mouse; D039503:Integrin alpha6; D060185:Tetraspanin 24; D004815:Epidermal Growth Factor