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 suppressed self-renewal related mammosphere formation and pluripotency marker expression

inhibited 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

ITGA2

knockdown in abolishing lung colonization of breast cancer cells. We identified that the low levels of

miR-206

as well as high expression levels of

ITGA2

ACLY

and

CCND1

are associated with an unfavorable relapse-free survival of the patients with estrogen receptor-negative or high grade breast cancer

especially basal-like or TNBC

possibly serving as potential biomarkers of cancer stemness and therapeutic targets of breast cancer metastasis.