Novel Molecular Targets for Ductal Carcinoma In Situ (DCIS)
Novel Molecular Targets for Ductal Carcinoma In Situ (DCIS)
This project is an immunohistochemical study of archived patient breast tissue, specifically
 pre-invasive lesion specimens. The purpose is the discovery of novel molecular markers of
 pre-invasive breast lesions. These novel markers, once validated in this study, can serve as
 targets for individualized prevention therapy, neoadjuvant therapy for ductal carcinoma in
 situ (DCIS), or predictors of lesion aggressiveness. We have discovered two novel classes of
 DCIS molecular pathways required for the survival of DCIS neoplastic cells that will serve as
 the basis for the candidate molecules to be evaluated in this proposed study. The first class
 of DCIS molecular markers is autophagy, a cell survival mechanism that we discovered to be
 highly augmented in the hypoxic and nutrient deprived intraductal neoplastic cells of human
 DCIS (1-4). The second class of biomarker is calcium efflux that is mediated in breast cells
 by the calcium export pump Plasma Membrane Calcium ATPase (PMCA2) (5, 6). During normal
 lactation, breast epithelium pumps large concentrations of calcium into milk. In neoplastic
 lesions, calcium is exported by PMCA2 as a cell survival mechanism, since cells under
 metabolic stress accumulate calcium to a toxic level. Calcium export in DCIS may also
 contribute to intraductal calcifications, a hallmark of high grade DCIS and the most common
 marker of DCIS on mammography (7).

 Sentara cares for hundreds of patients per year who are diagnosed with breast pre-invasive
 lesions, including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and
 lobular carcinoma in situ (LCIS). Sentara treats 25% of the women with breast cancer in
 Virginia. Coupled with information from the Sentara Cancer Registry, Dr. Hoefer or a research
 team member will identify eligible patients with ADH, DCIS, and/or LCIS at the time of the
 core biopsy diagnosis, surgical therapy, and/or upon lesion recurrence. After receiving
 written informed consent from the eligible patients, Sentara Pathology will retrieve the
 corresponding tissue blocks. The recut tissue sections will be processed at George Mason
 University, Center for Applied Proteomics and Molecular Medicine for markers relevant to
 calcium signaling, Vitamin D response, proliferation, autophagy and inflammation. Combined
 with the translational research expertise/technology in the Center for Applied Proteomics and
 Molecular Medicine at George Mason University, Sentara's diverse patient cohort provides an
 opportunity to address the most fundamental unanswered questions surrounding the etiology,
 progression, and therapy of pre-invasive breast lesions.
Sentara Healthcare is a progressive and integrated healthcare organization that cares for
 hundreds of patients per year who are diagnosed with breast cancer and pre-invasive lesions,
 including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and lobular
 carcinoma in situ (LCIS). Sentara Healthcare maintains a Cancer Registry which includes
 complete clinical information and disposition information of tissue blocks collected at the
 time of the core biopsy diagnosis, the surgical therapy, and upon lesion recurrence. Combined
 with the translational research expertise/technology in the Center for Applied Proteomics and
 Molecular Medicine (CAPMM) at George Mason University (GMU), the Sentara Healthcare extensive
 patient cohort provides an opportunity to address the most fundamental unanswered questions
 surrounding over-treatment and under-treatment of pre-invasive breast lesions:

 1. Does the histopathologic/molecular character of the carcinoma in situ, the immune
 infiltrate, and/or the stroma, correlate with the type of lesion (ADH, DCIS or LCIS),
 the grade of the lesion, or the presence of later recurrence?

 2. Does the level of autophagy within the lesion duct, or the level of PMCA2, of the
 pre-invasive lesion, correlate with lesion grade, the level of apoptosis, or the
 presence of later recurrence?

 3. Does the level of Vitamin D receptor correlate with the level of PMCA2?
Inclusion Criteria:

 -  Patients must be female, at least 18 years of age.

 -  Patients or their legally authorized representative must have signed and dated an
 informed consent form

 -  Patients must have at minimum, adequate samples of breast tissue available for use in
 this study.

 -  Patients with a tissue diagnosis of low, intermediate or high grade ductal carcinoma
 in situ or ductal carcinoma in situ with microinvasion.

 -  Patients with a diagnosis of atypical ductal hyperplasia, lobular cancer in situ or
 any preinvasive breast lesion.

 -  Patients with ductal carcinoma in situ undergoing either lumpectomy and radiation or
 mastectomy.

 -  Patients with a diagnosis of invasive ductal cancer.

 Exclusion Criteria:

 -  Male.

 -  Patients under the age of 18 or over the age of 89.

 -  Patient desires not to participate in the study.

 -  Inability to consent.