Elucidating the function of secreted maspin: inhibiting cathepsin D-mediated matrix degradation.
Cellular interaction with the extracellular milieu plays a significant role in normal biological and pathologic processes. Excessive degradation of basement membrane matrix by proteolytic enzymes is a hallmark of tumor invasion and metastasis, and aspartyl proteinase cathepsin D is implicated as a major contributor to this process. Maspin, a non-inhibitory serpin, plays an important role in mammary gland development and remodeling. Expression of Maspin is decreased in primary tumors and lost in metastatic lesions. Maspin is mostly cytoplasmic and is partially secreted; however, the fate and function of secreted Maspin has remained mostly unexplored. We hypothesized that secreted Maspin is incorporated into the matrix deposited by normal mammary epithelial cells and thus could play a critical role in cathepsin D-mediated matrix degradation and remodeling of mammary tissue. In the absence of Maspin, as is the case with most cancer cells, matrix degradation proceeds unrestricted, thus facilitating the progression to metastasis. To test this, we employed an in vitro model where gels containing both types I and IV collagen were preconditioned with normal mammary epithelial cells to allow the incorporation of secreted Maspin. This conditioned matrix was used to examine cathepsin D-mediated collagen degradation by human breast cancer cell lines. Our results indicate that secretion of Maspin and its deposition into the extracellular milieu play an important role in matrix degradation. In this capacity, Maspin could potentially regulate mammary tissue remodeling occurring under normal and pathologic conditions. In addition, these findings could have a potential effect on future therapeutic intervention strategies for breast cancer.
Khalkhali-Ellis
Zhila
Z
Children's Memorial Research Center and Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Chicago, IL 60614, USA. zellis@childrensmemorial.org
Hendrix
Mary J C
MJ
D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002402:Cathepsin D / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology / Q000378:metabolism*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D015843:Serpins / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship
C085344:SERPIN-B5; D015843:Serpins; D003094:Collagen; D002402:Cathepsin D