Identification of genes involved in the pathogenesis of breast cancer


This focus covers an interesting project carried out at the Department of Human Genome and Multifactorial Diseases by Ileana Zucchi and her group under the supervision of Renato Dulbecco. Its aim is the identification of genes involved in the pathogenesis of breast cancer, using the approach of Functional Genomics.

In order to address the genetic basis of mammary gland differentiation, we have exploited an experimental model based on two clonal derivatives, obtained from the rat mammary adenocarcinoma cell line RAMA-25. These derivatives 106 and LA7 have distinct differentiation potential since 106 cells do not undergo any type of differentiation either spontaneously or under the action of inducers, while LA7 cells can form branched structures on floating collagen gels that resemble ducts (early development of mammary gland), or hemispherical blisters called domes that we have shown to parallel an early stage of lactogenic differentiation occurring at pregnancy when epithelial cells are differentiated into alveoli (the lactogenic functional differentiated organ) (Zucchi et al, 2002). Dome formation can be strongly promoted in LA7 cells by differentiation-inducers such as: DMSO, lactogenic hormones, cAMP-analogs, retinoic acid and lipids and is accompanied by the expression of the milk protein genes (Zucchi et al, 2002).
By using transcriptoma technologies, we were able to identify genes which are differentially expressed in these two lines and demonstrated that they are essential for dome formation: the interferon inducible gene Rat8, the YMP gene, homologous to the human EMP3, and the gene encoding for the b-subunit of the amiloride-sensitive epithelial Na+ channel (ENaC) which play opposing roles in dome formation. These findings have been published (Zucchi et al, 1998; 1999). In addition, by using proteomic-based technologies, performed on LA7 and 106 cells under the same conditions, we found that for the formation of domes, down-regulation of maspin and expression of tropomyosin 5-b, annexin I and HSP90?{b are also required (Zucchi et al, 2001; 2002). In addition to these studies performed on cell lines, we plan to investigate human fresh tumor samples by a powerful transcriptoma technique, the serial analysis of gene expression (SAGE).

Relevant Publications

Zucchi I, Bini L, Albani D, Valaperta R, Liberatori S, Raggiaschi R, Montagna C, Susani L, Barbieri O, Pallini V, Vezzoni P, Dulbecco R. (2002). Proc Natl Acad Sci U S A. 99: 8660-5.

Zucchi I, Bini L, Valaperta R, Ginestra A, Albani D, Susani L, Sanchez JC, Liberatori S, Magi B, Raggiaschi R, Hochstrasser DF, Pallini V, Vezzoni P, Dulbecco R. (2001). Proc Natl Acad Sci U S A. 98:5608-13.

Zucchi I, Montagna C, Susani L, Montesano R, Affer M, Zanotti S, Redolfi E, Vezzoni P, Dulbecco R. (1999). Proc Natl Acad Sci U S A. 96:13766-70.

Zucchi I, Montagna C, Susani L, Vezzoni P, Dulbecco R. (1998). Proc Natl Acad Sci U S A. 95: 1079-84.

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