Molecular Pathway Traces Gene and Protein Activation in Breast Cancer

Cancer researchers have traced the molecular trail that links the ErbB2 (Her2/neu epidermal growth receptor family) oncogene to development of breast cancer via the activity of the Notch signaling pathway and its regulation of cyclin D1.

Approximately 25-30% of breast cancers have an amplification of the ErbB2 gene or overexpression of its protein product. Overexpression of this receptor in breast cancer is associated with increased disease recurrence and worse prognosis. The associated Notch gene belongs to a family of epidermal growth factor (EGF) like genes, which encode transmembrane proteins with a variable number of cysteine-rich EGF-like repeats in the extracellular region. Four notch genes have been described in mammals, which have been implicated in the differentiation of the nervous system and other structures.

According to results published in the September 10, 2008, online edition of the journal Clinical and Translational Science cyclin D1 is the critical connection between ErbB2 and Notch. The cyclin D protein belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Mutations, amplification, and overexpression of this gene, which alters cell cycle progression, were observed frequently in a variety of tumors and might contribute to tumorigenesis.

Investigators at Thomas Jefferson University (Philadelphia, PA, USA) used two methods to suppress cyclin D1 expression in a laboratory mouse population. Either deletion of cyclin D1 was obtained by genetic engineering, or small interfering RNA (siRNA) was used to silence cyclin D1 expression. In either case, Notch signaling was reduced. Reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of a protein called Numb, which is an endogenous inhibitor of Notch1 activity.

"Breast and other cancers are maintained through a population of cancer stem cells. By specifically targeting cancer stem cells we hope to reduce recurrence and improve therapy responses,” said senior author Dr. Richard Pestell, professor of cancer biology at Thomas Jefferson University.

Progressing towards that goal, this study has shown that cyclin D1 functions downstream as a genetic target of Notch1 and amplifies Notch1 activity by repressing Numb. This outlines a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.

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