Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional stu...Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.展开更多
基金This manuscript has been partially supported by NIH/NCI grants R00CA160638 and R01CA245699(H.L.),and Supple-ment for Diversity(V.A.),T32 CA080621-15(R.T.),and R01CA213843(R.A.K),American Cancer Society grant ACS127951-RSG-15-025-01-CSM(H.L.)the Susan G.Komen Foundation CCR15332826(H.L.)and CCR18548501(X.L.)+3 种基金the Department of Defense W81XWH-16-1-0021(H.L.)the Lynn Sage Cancer Research Foundation(X.L.and H.L.)North-western University’s Endocrinology Training Grant T32DK007169-39(A.H.)and start-up funds fromCaseWestern Reserve University and at Northwestern University(H.L.).
文摘Cancer metastasis is largely incurable and accounts for 90%of breast cancer deaths,especially for the aggressive basal-like or triple negative breast cancer(TNBC).Combining patient database analyses and functional studies,we examined the association of integrin family members with clinical outcomes as well as their connection with previously identified microRNA regulators of metastasis,such as miR-206 that inhibits stemness and metastasis of TNBC.Here we report that the integrin receptor CD49b-encoding ITGA2,a direct target of miR-206,promotes breast cancer stemness and metastasis.ITGA2 knockdown sup-pressed self-renewal related mammosphere formation and pluripotency marker expression,in-hibited cell cycling,compromised migration and invasion,and therefore decreased lung metastasis of breast cancer.ITGA2 overexpression reversed miR-206-caused cell cycle arrest in G1.RNA sequencing analyses revealed that ITGA2 knockdown inhibits genes related to cell cycle regulation and lipid metabolism,including CCND1 and ACLY as representative targets,respectively.Knockdown of CCND1 or ACLY inhibits mammosphere formation of breast cancer cells.Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest.ACLY-encoded ATP citrate lyase is essential to maintain cellular acetyl-CoA levels.CCND1 knockdown further mimics 1TGA2 knodkdown in abolishing lung colonization of breast cancer cells.We identified that the low levels of miR-206 as well as high expression levels of 1TGA2,ACLY and CCND1 are associated with an unf avor able relapse-free survival of the pa-tients with estrogen receptor-negative or high grade breast cancer,especially basal-like or TNBC,possibly serving as potential biomarkers of cancer stemness and thera peutic targets of breast cancer metastasis.
