Hematopoiesis and breast epithelial proliferation and differentiation represent processes of terminal differentiation leading to cell death in the case of hematopoiesis and of reversible differentiation and proliferation in the case of the breast epithelium. When viewed in the context of aging, each mimics aspects of cellular aging where other factors such as number of cell divisions and oxidant stress and damage are thought to limit cellular life span but nonetheless are likely to have effects through many of the same cell signaling processes. When viewed in the context of the treatment of malignant diseases, pharmacologic manipulation of signaling pathways responsible for controlling the balance between differentiation, proliferation and cell death in conjunction with chemotherapeutic agents may well provide methods to increase the specificity of conventional agents thus increasing both efficacy and reducing toxicity. Both are critical components needed to improve treatment in patients with co-morbidities most frequently associated with aging where the balance between benefit vs risk of intervention becomes increasingly problematic with age. CDNA micro-arrays are being utilized to examine global expression changes in estrogen responsive breast epithelial proliferation using the MCF-7 and T47D human breast tumor cell models with comparison to estrogen unresponsive cells such as MDA-MB-231. Multiple changes have been identified including differences in expression of IGF-2, annexin-5, cyclin N1, cadherins and death associated protein 3. In addition, a critical change previously identified is being analyzed in greater depth, that of estrogen induced regulation of the transcription factor proto-oncogene c-myb. Interest in c-myb in breast epithelium and tumors derives from the finding that c-myb is expressed in more than 60% of clinical breast tumor specimens and that, while expression is positively correlated with estrogen receptor (ER) and progesterone receptor (PR) status, significant numbers (approx. 30%) of ER-/PR- tumors also express myb. The laboratory has begun to examine consequences of expression in both ER+ and - tumor cell lines. An important question from a biologic perspective is what effect myb expression has on breast tumor cell behavior. In the case of myb expression in ER+ cell lines, transfectants are being developed to constitutively express the 72 kd form of c-myb. The hypothesis to be tested is that a specific function of c-myb in some breast epithelial cell types is stimulation of IGF-1 and IGF-1R expression. Thus, constitutive expression of c-myb would be expected to make cells such as MCF-7 estrogen independent and resistant to antiestrogens such as Tamoxifen. If true, then Tamoxifen resistance could occur through any mechanism that would uncouple estrogen regulation from myb expression. Development of this breast tumor model will also provide an epithelial cell system for elucidation of transcription targets of c-myb action and whether these are lineage and/or tissue specific when compared with those of the hematopoietic system and provide an important dimension to work examining chemotherapeutic agent effects coupled with modification of signal transduction pathways in proliferation, differentiation and cell death.
