HMG-I(Y) recognizes base-unpairing regions of matrix attachment sequences and its increased expression is directly linked to metastatic breast cancerphenotype

Base-unpairing regions (SURs) contain a specialized DNA context with an exc eptionally high unwinding propensity, and are typically identified within v arious matrix attachment regions. A BUR affinity column was used to purify a doublet of M-r 20,000 proteins from human breast carcinoma cells. These p roteins were identified as the high-mobility group (HMG) protein, HMG-I, an d its splicing variant, HMG-Y. We show that HMG-I(Y) specifically binds BUR s. Mutating BURs so as to abrogate their unwinding property greatly reduced their binding affinity to HMG-I(Y), Numerous studies have indicated that e levated HMG-I(Y) expression is correlated with more advanced cancers and wi th increased metastatic potential. We studied whether the expression of HMG -I(Y) responds to signaling through the heregulin (HRG)-erbB pathway and th e extracellular matrix. HMG-I(Y) expression was increased in MCF-7 cells af ter stable transfection with an HRG expression construct that led cells to acquire estrogen independence and metastasizing ability. A high level of HM G-I(Y) expression was detected in metastatic MDA-MB-231 cells, but the expr ession was virtually diminished, and the metastasizing ability was lost aft er cells were stably transfected with an antisense HRG cDNA construct. HMG- I(Y) was also decreased in MDA-MB-231 cells when treated with a chemical in hibitor for matrix metalloproteinase-9 that led to a reduction of invasive capability in vitro. The level of HMG-I(Y) expression, therefore, is dynami cally regulated in human breast cancer cells in response to varying types o f signaling that affect metastatic ability, including the HRG-erbB pathway and those from the extracellular matrix.