Margaret A. Shupnik, PhD

Margaret A. Shupnik, PhD

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Estrogen receptor (ER) action in gene transcription and cell proliferation; estrogen receptor subtype-specific actions and cross-talk with intracellular signaling pathways

Cancer-related research in the Shupnik lab is concentrated on steroid-dependent cancers of the reproductive organs (breast and uterus) and neuroendocrine (pituitary) cells, and particularly on the role of estrogen and estrogen receptors in the development of these cancers.  Joint investigations with Dr. Corinne Silva (Endocrine program), funded in part by a new Komen Foundation award, are focused on the cross talk between the ER, EGF-receptor and the STAT transcription factors in mediating cell proliferation in breast cancer cells.  The STATS are phosphorylated in response to both estrogen and EGF, and estrogen treatment regulates transcription of STAT-controlled genes.  The c-Src dependent phosphorylation of the EGFR at tryosine 845 is required for proliferative responses to estrogen and for increased STAT activity. Collaborative studies with Dr. Amy Bouton (Microbiology) on tamoxifen-resistant breast cancer demonstrated that overexpression of the signaling molecules Cas, and AND-34 promote tamoxifen resistance and estrogen-independence, potentially by activation of c-Src and dramatic increases in STAT5 activity. These studies suggest therapeutic tools to regulate the STATs could be effective in steroid-dependent and steroid-independent breast cancers, and form the basis of two submitted manuscripts and a project on a newly submitted breast cancer program project on therapeutic resistance in breast cancer (S. Parsons, PI).  The laboratory also identified an estrogen-regulated neuroendocrine-specific isoform of ERa (TERP) that is transcribed from an intronic promoter, and which acts as a dominant-negative receptor on estrogen-stimulated gene transcription. Because TERP appears is expressed in normal tissue, but is lost in pituitary tumors such as prolactinomas, it is postulated that one function of TERP is to modulate cell proliferation in response to estrogen. Studies on uterine carcinoma showed that In cell culture and transcription studies, the presence of a variant receptor (ERaD5) - a splice variant protein found at significant levels only in endometrial cancer - dramatically increases basal transcription from estrogen-regulated genes while decreasing the requirement for estrogen.

Collaborative studies include work with Drs. Song and Santen (Internal Medicine) to demonstrate estrogen-sensitive activation of MAPK through direct interactions of ERa with the adaptor molecule Shc.  These extranuclear effects have consequences on breast cancer cell function, in enhancing growth responses to lower estrogen levels.  Additional studies with the Rice laboratory identified alterations in the estrogen and progesterone receptor (PR) profile in normal human uterine tissue compared to endometrial cancers, including the loss of ERb expression in postmenopausal compared to premenopausal women, and in endometrial tumors, both Grade I and MMMT.