Key Research Developments

Defining the role of retinoid signaling in early mammary carcinogenesis:

Loss of retinoic acid receptor-beta2 (RARβ2) function is an early event in mammary carcinogenesis and the normal appearing epithelial cells adjacent to invasive breast cancer exhibit loss of RARβ2 expression.  These observations suggest that loss of RARβ2 function may provide a local environment that promotes mammary carcinogenesis.  My laboratory has made several important observations defining how loss of RARβ2 function may promote survival of damaged mammary epithelial cells.  We were the first investigators to observe that while RARβ2 promotes growth regulation in normal mammary epithelial cells, RARβ2 mediates apoptosis in breast cancer cells.  Next we observed that loss of RARβ2 function in three-dimensional prepared extracellular matrix culture (rECM) promotes dysregulated growth and blocks the formation of a polarized epithelium.  This is potentially a very important observation because we have subsequently shown that suppression of RARβ2 function block rECM-growth arrest and polarity signals and thereby promotes survival of damaged mammary epithelial cells. 

Defining the role of integrin-signaling in early mammary carciogenesis:

Interactions between epithelial cells and extracellular matrix play a critical role in maintaining normal tissue homeostasis; we hypothesize that these interactions are disrupted during the initiation of breast cancer.  In our in vitro model of early mammary carcinogenesis, we observe that α3/β1-integrin and its receptor laminin-5 1) play an important role in rECM-growth regulation and -polarity and 2) are critical for targeting the apoptotic elimination of acutely damaged mammary epithelial cells.  Suppression of α3/β1-integrin-signaling or laminin-5 expression in normal human mammary epithelial cells resulted in loss of growth regulation and polarity in rECM culture.   This work is funded by R01 CA88799.

Identifying an extragenomic mechanism of tamoxifen-signaling in damaged mammary epithelial cells:

Although the molecular mechanism of tamoxifen-action in breast cancer cells that express high levels of estrogen receptor  (ER+) is well studied, there is little information on how tamoxifen may act in non-cancerous human breast tissue that normally expresses low levels of ER (ER-“poor”). The “classic” or genomic mechanism of steroid-action requires the presence of ER and both transcription and translation.  We were the first group to report that tamoxifen acts through a “non-classic” mitochondrial-signaling pathway to promote apoptosis in damaged ER-“poor": normal human mammary epithelial cells.  We have subsequently demonstrated that apoptosis is initiated through cell surface estrogen-binding sites that regulate Akt-phosphorylation and promote mitochondrial membrane depolarization.  This work is currently funded by R01 CA984441.



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