Constitutive Activation of Smoothened (SMO) Enhances MMTV-c-ErbB2-Induced, but Not MMTV-Wnt1-Induced, Mammary Tumorigenesis.

Abstract

Abstract Background. Smoothened (Smo) is a key effector protein in the hedgehog signaling pathway, a developmental pathway involved in the regulation of pattern formation, proliferation, cell fate, and stem/progenitor cell function in the mammary gland. In human clinical samples, altered hedgehog signaling occurs early in breast cancer development with SMO ectopically expressed in 70% of DCIS and 30% of IBC. Coupled with our genetic studies in mice, these clinical observations suggest a causal or contributory role in breast cancer.Materials and Methods. To determine whether activation of SMO is oncogenic in the mammary gland, and to study possible interactions between hedgehog signaling and other oncogenic signaling pathways, we crossed transgenic mice expressing a constitutively active form of Smo (SmoM2) under the Mouse Mammary Tumor Virus promoter (MMTV-SmoM2) with mice expressing either MMTV-Wnt1 or MMTV-c-ErbB2. Time to tumor onset, tumor growth, and tumor multiplicity were measured, and resulting tumors evaluated histologically.Results. Expression of MMTV-SmoM2 was not oncogenic as a single genetic alteration. In genetic crosses, simultaneous expression of MMTV-Wnt1 and MMTV-SmoM2 within mammary epithelium did not affect tumor formation. However, simultaneous expression of MMTV-c-ErbB2 and MMTV-SmoM2 resulted in significantly accelerated median time to tumor formation, with an overall tumor formation rate of 100% compared to MMTV-c-ErbB2 alone (74%).Discussion. Activated SMO is not oncogenic under the conditions tested. However, MMTV-SmoM2 interacts genetically with MMTV-c-ErbB2, but not MMTV-Wnt1 to promote mammary tumorigenesis. Together, our data indicate a contributory role for Smo in breast cancer progression and suggest that hedgehog signaling inhibitors may be useful for treatment of a subset of human breast cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3152.